The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index; 9 of the 102 sources its claims cite were checked for support.
Exercise Training Improves Tumor Control by Increasing CD8+ T-cell Infiltration via CXCR3 Signaling and Sensitizes Breast Cancer to Immune Checkpoint Blockade
Open accessPublished version of a preprint
Abstract
The mechanisms behind the antitumor effects of exercise training (ExTr) are not fully understood. Using mouse models of established breast cancer, we examined here the causal role of CD8+ T cells in the benefit acquired from ExTr in tumor control, as well as the ability of ExTr to improve immunotherapy responses. We implanted E0771, EMT6, MMTV-PyMT, and MCa-M3C breast cancer cells orthotopically in wild-type or Cxcr3−/− female mice and initiated intensity-controlled ExTr sessions when tumors reached approximately 100 mm3. We characterized the tumor microenvironment (TME) using flow cytometry, transcriptome analysis, proteome array, ELISA, and immunohistochemistry. We used antibodies against CD8+ T cells for cell depletion. Treatment with immune checkpoint blockade (ICB) consisted of anti–PD-1 alone or in combination with anti–CTLA-4. ExTr delayed tumor growth and induced vessel normalization, demonstrated by increased pericyte coverage and perfusion and by decreased hypoxia. ExTr boosted CD8+ T-cell infiltration, with enhanced effector function. CD8+ T-cell depletion prevented the antitumor effect of ExTr. The recruitment of CD8+ T cells and the antitumor effects of ExTr were abrogated in Cxcr3−/− mice, supporting the causal role of the CXCL9/CXCL11–CXCR3 pathway. ExTr also sensitized ICB-refractory breast cancers to treatment. Our results indicate that ExTr can normalize the tumor vasculature, reprogram the immune TME, and enhance the antitumor activity mediated by CD8+ T cells via CXCR3, boosting ICB responses. Our findings and mechanistic insights provide a rationale for the clinical translation of ExTr to improve immunotherapy of breast cancer.
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62 Own result · 47 Not checked yet · 22 Own interpretation · 10 Own method · 5 No basis given · 3 Partly supported · 1 Supported so far · accuracy not yet measured
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In the paper
“We previously demonstrated that vascular normalization could increase immune cells’ infiltration into tumors, and multiple studies have confirmed these findings in several tumor models (15,17-19).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Supportedcites [15] Huang, 2012, Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy, Proc Natl Acad Sci U S A source
The Abstract reports that vascular-normalizing lower doses of anti-VEGFR2 antibody facilitated CD4+ and CD8+ T-cell infiltration into tumors in murine breast cancer models. The Discussion likewise says lower-dose treatment normalized tumor vasculature and created a microenvironment that recruited CD8+ T cells. These findings support the claim that vascular normalization can increase immune-cell infiltration. (LLM, conf=0.93)
- Supportedcites [17] Zheng, 2018, Increased vessel perfusion predicts the efficacy of immune checkpoint blockade, J Clin Invest source
The Discussion states that increased vessel perfusion and reduced hypoxia may facilitate CD8+ T-cell infiltration into tumors. The paper also reports increased CD8+ T-cell infiltration alongside improved vessel perfusion after checkpoint blockade in tumor models. The proposed effect is framed as a possibility, consistent with the claim’s “can.” (LLM, conf=0.85)
- Supportedcites [18] Tian, 2017, Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming, Nature source
The paper states that vessel normalization recruits T lymphocytes and that disrupting it reduces their infiltration (Abstract). It also reports that increased pericyte coverage was accompanied by greater infiltration of host immune cells, an effect attenuated by pericyte depletion (Abstract; Extended Data Figure 10). (LLM, conf=0.93)
- Not checked yetcites [19] Schmittnaegel, 2017, Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade, Sci Transl Med source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This may explain, at least in part, why previous preclinical studies failed to show antitumor activity under similar ExTr protocols (7,52,56).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Partly supportedcites [7] Schadler, 2016, Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy, Oncotarget sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports that exercise alone had no effect on prostate tumor growth in mice, and the Results (page unavailable) report no significant effect on PDAC tumor growth. These passages support the point that some preclinical exercise studies found no antitumor effect, but the paper does not attribute those outcomes to strain differences in relative exercise intensity or establish that the earlier protocols were similar. (LLM, conf=0.83)
- Partly supportedcites [52] Colbert, 2009, Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer, Med Sci Sports Exerc sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports that these mice ran less than mice of other strains and suggests that insufficient exercise volume might explain the lack of a beneficial effect. It does not establish a strain difference in relative exercise intensity; the authors say they did not measure exercise intensity or fitness. (LLM, conf=0.82)
- Partly supportedcites [56] Glass, 2017, Differential response to exercise in claudin-low breast cancer, Oncotarget sourceExperimental — accuracy not yet measured
The Introduction reports that some preclinical breast-tumor studies found no growth inhibition with exercise, and the Results found no tumor response in the 4TO7 model. But the paper does not attribute earlier null results to strain differences in relative exercise intensity. Its Results instead report uniform exercise-dose delivery across its models, while the Discussion suggests tumor metabolism or an insufficient prescription for 4TO7 as possible explanations. (LLM, conf=0.85)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CD8+ T-cell depletion prevented the antitumor effect of ExTr.”
- Also stated in: § CD8+ T cells are necessary for the antitumor effect of ExTr · hedged
“CD8+ T-cell depletion completely abrogated ExTr-induced tumor growth delay (Fig. 5B–C; individual values and time to triple tumor volume in Supplementary Fig. S9A-D; comparison between tumor growth curve from anti-CD8 and IgG in Supplementary Fig. S9E), indicating that CD8+ T cells’ tumor-infiltration is necessary for the antitumor effect of ExTr.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § CD8+ T cells are necessary for the antitumor effect of ExTr · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The recruitment of CD8+ T cells and the antitumor effects of ExTr were abrogated in Cxcr3−/− mice, supporting the causal role of the CXCL9/CXCL11-CXCR3 pathway.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr induced a metabolic reprogramming by reducing glucose uptake/insulin pathways and upregulated several gene sets associated with oxidative metabolism, such as oxidative phosphorylation (OXPHOS).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr reprograms the transcriptional signature of the TME
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr led to an increased percentage of vessels associated with αSMA+ perivascular cells (Fig. 2C–D), an indicator of vascular normalization.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr normalizes the tumor vasculature and TME
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr also sensitized ICB-refractory BCs to treatment.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: An abnormal tumor microenvironment caused partly by poor perfusion excludes CD8+ T cells and reduces the effect of immunotherapies such as immune checkpoint blockade.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr also increased the fraction of vessels that were perfused (Fig. 2E–F), indicating improved vascular function.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr normalizes the tumor vasculature and TME
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr did not change vessel density (Fig. 2A-B) but promoted tumor vessels’ maturation.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr normalizes the tumor vasculature and TME
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr induced a metabolic reprogramming by reducing glucose uptake/insulin pathways and upregulated several gene sets associated with oxidative metabolism, such as oxidative phosphorylation (OXPHOS).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr reprograms the transcriptional signature of the TME
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It also enhanced gene expression linked to cytokine activation and downregulated several pathways involved with immunosuppression in BC (20,40,41), whose inhibition is demonstrated in the clinic to synergize with anti-PD-1 against solid tumors (42).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr reprograms the transcriptional signature of the TME
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“It also enhanced gene expression linked to cytokine activation and downregulated several pathways involved with immunosuppression in BC (20,40,41), whose inhibition is demonstrated in the clinic to synergize with anti-PD-1 against solid tumors (42).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr reprograms the transcriptional signature of the TME
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“More functional vessels resulted in reduced hypoxia (Fig. 2G–H), indicating normalization of TME.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr normalizes the tumor vasculature and TME
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The proliferation marker Ki67 was elevated in ExTr groups (Fig. 4E–F).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The recruitment of CD8+ T cells and the antitumor effects of ExTr were abrogated in Cxcr3−/− mice, supporting the causal role of the CXCL9/CXCL11-CXCR3 pathway.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ExTr increased the fraction of effector CD8+ T cells expressing granzyme B (Fig. 4G–H and) and IFNγ (Fig. 4I–J).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We found via GSEA that in the ExTr group, there was upregulation of transcriptional pathways consistent with antitumor immune activity and vessel normalization in the BC patients (Fig. 3C–D), similar to what we found in mice.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr reprograms the transcriptional signature of the TME
What the sources say
- Not checked yetcites [38] Ligibel, 2019, Impact of a pre-operative exercise intervention on breast cancer proliferation and gene expression: results from the Pre-Operative Health and Body (PreHAB) Study, Clin Cancer Res source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr boosted CD8+ T-cell infiltration, with enhanced effector function.”
- Also stated in: § ExTr increases the infiltration of CD8+ T cells into BC TME · plain
“we found that ExTr increased the infiltration of CD8+ T cells into the BC TME (Fig. 4A-D, Supplementary Fig. S6A–B).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § ExTr increases the infiltration of CD8+ T cells into BC TME · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and IFNγ (Fig. 4I–J).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ExTr delayed tumor growth and induced vessel normalization, demonstrated by increased pericyte coverage and perfusion, and decreased hypoxia.”
- Also stated in: § ExTr delays tumor growth in established BCs · plain
“Using different models, we showed that ExTr delayed tumor growth in BC.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § ExTr delays tumor growth in established BCs · plain
In the paper
“We found via GSEA that in the ExTr group, there was upregulation of transcriptional pathways consistent with antitumor immune activity and vessel normalization in the BC patients (Fig. 3C–D), similar to what we found in mice.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr reprograms the transcriptional signature of the TME
What the sources say
- Not checked yetcites [38] Ligibel, 2019, Impact of a pre-operative exercise intervention on breast cancer proliferation and gene expression: results from the Pre-Operative Health and Body (PreHAB) Study, Clin Cancer Res source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“There was no change in CXCL10 in both models (Fig. 6C).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Majority of the CD8+ T cells expressed IFNγ+, and there was no difference between groups (Fig. 6J).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The depletion of CD8+ T cells abolished the antitumor effect of ExTr, confirming that the mechanism of antitumor activity from ExTr is CD8+ T cell-dependent.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ExTr also increased the total number of intratumoral granzyme B+CD8+ T cells with ExTr, although the fraction of granzyme B+CD8+ T cells was increased only in the ExTr+ICB group (Fig. 7E–H).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr improves immune checkpoint blockade therapy in BC
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Loss of Cxcr3 completely abolished antitumor effects of ExTr, as assessed by tumor growth kinetics and final tumor weight at day 11 (Fig. 6F–G).”
- Also stated in: § Discussion · boosted
“ExTr antitumor effect was entirely abolished in Cxcr3−/− mice, demonstrating that the CXCR3 pathway participates in the antitumor effect of ExTr.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Discussion · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further analysis indicated similar infiltration of CD8+ T cells in both groups subjected to ExTr (Fig. 7D–G).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr improves immune checkpoint blockade therapy in BC
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“The higher the increase in maximal aerobic exercise capacity (a biomarker of response to ExTr), the higher was the infiltration of CD8+ TILs (Supplementary Fig. S6D).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr increases the infiltration of CD8+ T cells into BC TME
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We also observed that ExTr increased the absolute number of CD8+ T cells expressing CXCR3 more than 3-fold in MCa-M3C (p<0.05) and 2-fold in the E0771 (p=0.07) tumor (Fig. 6E).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“CXCL9+ immune cells were predominantly macrophages (Supplementary Fig. S10H–I).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CXCL9 also showed a trend towards increase in MCa-M3C (Fig. 6B).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr induced a small but significant increase in CD8+ T cells in Cxcr3-KO mice, suggesting CXCR3-independent mechanisms of CD8+ T-cell recruitment (Fig. 6H–I).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We also observed that ExTr increased the absolute number of CD8+ T cells expressing CXCR3 more than 3-fold in MCa-M3C (p<0.05) and 2-fold in the E0771 (p=0.07) tumor (Fig. 6E).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our study demonstrated that the relative exercise intensity for C57BL/6 versus FVB female mice are distinct.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“However, ExTr significantly increased the total number of CD8+ T cells, contributing to the increased number of exhausted PD-1+CTLA-4+ T cells within the tumors (Supplementary Fig. S8F).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ExTr also prevented cancer-induced fatigue in ICB-treated mice (Supplementary Fig. S11G).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr improves immune checkpoint blockade therapy in BC
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We found a significant variability of ExTr dose within preclinical models, even though it is usually assumed that the same ExTr velocity would fit all mouse strains and experimental conditions.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that ExTr significantly reduced CD8+ T cells showing an exhausted phenotype in E0771 and did not change the percentage in MCa-M3C (Supplementary Fig. S8E).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“We found ExTr reduced the amount of CD8+CTLA-4+ in MCa-M3C tumors and CD8+LAG3+ in E0771 tumors.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“indicated by the increased number of infiltrating CD8+ T cells per field (Fig. 4D).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr increases the infiltration of CD8+ T cells into BC TME
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, due to the increased total CD8+ T-cell recruitment in ExTr mice tumors, the number of exhausted CD8+ T cells also increased proportionally.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr improves immune checkpoint blockade therapy in BC
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ExTr consistently boosted CD8+ T-cell infiltration, indicated by changes in relative (Fig. 4A) and absolute numbers (Fig. 4B) of CD8+ TILs.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr increases the infiltration of CD8+ T cells into BC TME
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We found no effect of ICB alone in the orthotopic BCs (Fig. 7B-C, Supplementary Fig. S11).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr improves immune checkpoint blockade therapy in BC
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“we conducted a proteome profile array of bulk tumors, and identified CXCL9 and CXCL11 as potential candidates (Fig. 6A, Supplementary Fig. S10).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Unlike the voluntary running model, in which mice can run 20 km per day (51), our treadmill model’s exercise volume is 10-20 times less than this.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [51] Manzanares, 2018, Voluntary wheel running: patterns and physiological effects in mice, Braz J Med Biol Res source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“ExTr also increased the total number of intratumoral granzyme B+CD8+ T cells with ExTr, although the fraction of granzyme B+CD8+ T cells was increased only in the ExTr+ICB group (Fig. 7E–H).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr improves immune checkpoint blockade therapy in BC
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found ExTr reduced the amount of CD8+CTLA-4+ in MCa-M3C tumors and CD8+LAG3+ in E0771 tumors.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, ExTr significantly increased the total number of CD8+ T cells, contributing to the increased number of exhausted PD-1+CTLA-4+ T cells within the tumors (Supplementary Fig. S8F).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of CD8+ T cells in E0771 tumors grown in Cxcr3−/− mice was 10-fold lower than that observed in wild-type mice after 7 days of ExTr (Fig. 6H).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found ExTr significantly increased CXCL9 in E0771 and CXCL11 in the MCa-M3C model (Fig. 6B–D).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that ExTr significantly reduced CD8+ T cells showing an exhausted phenotype in E0771 and did not change the percentage in MCa-M3C (Supplementary Fig. S8E).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Changes in tumor volume were inversely correlated with CD8+ TIL density (Supplementary Fig. S6C).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr increases the infiltration of CD8+ T cells into BC TME
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we found that ExTr increased the intratumoral distribution of CD8+ T cells within the TME (Fig. 4C)”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr increases the infiltration of CD8+ T cells into BC TME
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr also increased the number of non-immune cells expressing PD-L1 (Supplementary Fig. S8C).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr enhances the effector function of CD8+ T cells
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found ExTr significantly increased CXCL9 in E0771 and CXCL11 in the MCa-M3C model (Fig. 6B–D).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The frequency of CD8+ T cells was also lower in Cxcr3−/− mice (Fig. 6I).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“This velocity would have represented ~35% of maximal running capacity for C57BL/6 mice in our study, instead of 60%.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
hedged- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Indeed, a large number of infiltrating CD8+ T cells expressed IFNγ in Cxcr3−/− mice.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Our work shows that ExTr and ICB synergistically enhance the activity of effector CD8+ T cells (i.e., a fraction of IFNγ- or granzyme B-expressing CD8+ T cells).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ExTr increased the number of cells expressing PD-L1, a biomarker of response for metastatic BC (25).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [25] Savas, 2018, Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis, Nat Med source
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr increases CD8+ T cells by reprogramming the TME towards a less aggressive phenotype, but a large fraction of CD8+ T cells remain expressing immune checkpoint receptors, suggesting these tumors would benefit from ICB therapy.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr increases CD8+ T cells by reprogramming the TME towards a less aggressive phenotype, but a large fraction of CD8+ T cells remain expressing immune checkpoint receptors, suggesting these tumors would benefit from ICB therapy.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A varying degree of infiltrating CD8+ T cells express multiple immune checkpoints (e.g., co-expression of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)), which cause these cells to become exhausted (26).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [26] Beavis, 2018, Dual PD-1 and CTLA-4 checkpoint blockade promotes antitumor immune responses through CD4(+)Foxp3(-) cell-mediated modulation of CD103(+) dendritic cells, Cancer Immunol Res source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As a consequence, the TME becomes less hypoxic, rendering tumors less aggressive (14).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [14] Incio, 2018, Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2, Sci Transl Med source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Because exercise is a homeostatic physiological intervention, it also affects the tumor microenvironment (TME) (5-10).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [5] McCullough, 2014, Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise, J Natl Cancer Inst source
- Not checked yetcites [6] Betof, 2015, Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise, J Natl Cancer Inst source
- Not checked yetcites [7] Schadler, 2016, Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy, Oncotarget source
- Not checked yetcites [8] Pedersen, 2016, Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution, Cell Metab source
- Not checked yetcites [9] Miller, 2016, Perfusion pressure is a critical determinant of the intratumoral extravasation of oncolytic viruses, Mol Ther source
- Not checked yetcites [10] Rundqvist, 2020, Cytotoxic T-cells mediate exercise-induced reductions in tumor growth, Elife source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“any transient increase in mean arterial pressure, as seen during exercise, increases tumor perfusion (13).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [13] Zlotecki, 1995, Pharmacologic modification of tumor blood flow and interstitial fluid pressure in a human tumor xenograft: network analysis and mechanistic interpretation, Microvasc Res source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Limited T-cell recruitment and function in the TME correlates with poor prognosis in BC (21,22).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [21] Chung, 2017, Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer, Nat Commun source
- Not checked yetcites [22] Denkert, 2018, Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy, Lancet Oncol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“An improved vascular network favors adaptive antitumor immunity by promoting trafficking and re-localization of tumor-infiltrating lymphocytes (TILs), leading to improved outcomes of various immunotherapies, including immune checkpoint blockade (ICB) (15-20).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [15] Huang, 2012, Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy, Proc Natl Acad Sci U S A source
- Not checked yetcites [16] Ashcraft, 2019, Exercise as adjunct therapy in cancer, Semin Radiat Oncol source
- Not checked yetcites [17] Zheng, 2018, Increased vessel perfusion predicts the efficacy of immune checkpoint blockade, J Clin Invest source
- Not checked yetcites [18] Tian, 2017, Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming, Nature source
- Not checked yetcites [19] Schmittnaegel, 2017, Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade, Sci Transl Med source
- Not checked yetcites [20] Chen, 2019, Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer, Proc Natl Acad Sci U S A source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“with enhanced effector function.”
- Also stated in: § ExTr enhances the effector function of CD8+ T cells · plain
“ExTr enhances the effector function of CD8+ T cells”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Also stated in: § ExTr enhances the effector function of CD8+ T cells · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“induced vessel normalization, demonstrated by increased pericyte coverage and perfusion, and decreased hypoxia.”
- Also stated in: § ExTr normalizes the tumor vasculature and TME · plain
“ExTr induced vessel normalization in both E0771 and MCa-M3C BC models.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
- Also stated in: § ExTr normalizes the tumor vasculature and TME · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“supporting the causal role of the CXCL9/CXCL11-CXCR3 pathway.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Preclinical studies indicate that tumor perfusion and oxygenation increase from the very first exercise session (5,9,11).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [5] McCullough, 2014, Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise, J Natl Cancer Inst source
- Not checked yetcites [9] Miller, 2016, Perfusion pressure is a critical determinant of the intratumoral extravasation of oncolytic viruses, Mol Ther source
- Not checked yetcites [11] Garcia, 2016, Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity, J Appl Physiol (1985) source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that CD8+ T cells’ tumor-infiltration is necessary for the antitumor effect of ExTr.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CD8+ T cells are necessary for the antitumor effect of ExTr
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“More importantly, the lack of proper control of exercise dose might account for the large variability and absence of significant results from exercise interventions in clinical trials (2).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [2] Iyengar, 2019, Development of exercise as interception therapy for cancer: a review, JAMA Oncol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“It seems only supervised ExTr, accounting for planned interventions considering both duration and intensity, has been proven beneficial (3,53-55).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [3] Williams, 2014, Significantly greater reduction in breast cancer mortality from post-diagnosis running than walking, Int J Cancer source
- Not checked yetcites [53] Park, 2015, The effect of oncologists' exercise recommendations on the level of exercise and quality of life in survivors of breast and colorectal cancer: a randomized controlled trial, Cancer source
- Not checked yetcites [54] Buffart, 2017, Effects and moderators of exercise on quality of life and physical function in patients with cancer: an individual patient data meta-analysis of 34 RCTs, Cancer Treat Rev source
- Not checked yetcites [55] Sweegers, 2018, Which exercise prescriptions improve quality of life and physical function in patients with cancer during and following treatment? A systematic review and meta-analysis of randomised controlled trials, Br J Sports Med source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The problem is that, along with the much larger exercise volume that does not recapitulate human exercise behavior, the running wheel model does not provide a reliable preclinical model on the therapeutic ExTr either.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Previous therapeutic ExTr interventions (i.e., starting treatment when tumors were established) on running treadmills could not demonstrate enhancement of cytotoxic NK nor CD8+ T cells (7,52,56).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [7] Schadler, 2016, Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy, Oncotarget source
- Not checked yetcites [52] Colbert, 2009, Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer, Med Sci Sports Exerc source
- Not checked yetcites [56] Glass, 2017, Differential response to exercise in claudin-low breast cancer, Oncotarget source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Emerging data suggest that exercise dose plays a significant role in modulating tumor physiology (2,52).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The depletion of CD8+ T cells abolished the antitumor effect of ExTr, confirming that the mechanism of antitumor activity from ExTr is CD8+ T cell-dependent.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This is probably due to differences in exercise intensity.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, these CD8+ T cells were not enough to induce tumor control.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr induced a small but significant increase in CD8+ T cells in Cxcr3-KO mice, suggesting CXCR3-independent mechanisms of CD8+ T-cell recruitment (Fig. 6H–I).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, it better recapitulates ExTr in patients participating in clinically supervised ExTr programs.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Because most previous preclinical studies use ad libitum physical activity models (6,8,10), which do not properly capture human exercise behavior, we adapted a controlled exercise.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [6] Betof, 2015, Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise, J Natl Cancer Inst source
- Not checked yetcites [8] Pedersen, 2016, Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution, Cell Metab source
- Not checked yetcites [10] Rundqvist, 2020, Cytotoxic T-cells mediate exercise-induced reductions in tumor growth, Elife source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the synergism between induced vessel normalization and CD8-mediated tumor control seems to occur when sufficient intensity (i.e., from moderate-to-vigorous) of ExTr is reached.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This may explain why CD8+CXCR3+ T cells are required for improved response to immunotherapy.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“These authors did not observe changes in tumor growth or immune cell infiltration with the low-intensity ExTr.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [7] Schadler, 2016, Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy, Oncotarget source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Naïve and memory subsets of CD8+ T cells are increased only beyond moderate-to-vigorous exercise intensity sessions (58).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [58] Campbell, 2009, Acute exercise mobilises CD8+ T lymphocytes exhibiting an effector-memory phenotype, Brain Behav Immun source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr antitumor effect was entirely abolished in Cxcr3−/− mice, demonstrating that the CXCR3 pathway participates in the antitumor effect of ExTr.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“This shift can occur as a consequence of enhanced tumor perfusion due to vessel normalization (60).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [60] Navarro, 2016, Targeting tumor mitochondrial metabolism overcomes resistance to antiangiogenics, Cell Rep source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Thus, a metabolic switch towards less hypoxic and more oxidative metabolism that favors CD8+ T-cell effector function (62) might have facilitated the enhanced CD8+ T cell effector function with ExTr.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [62] Calcinotto, 2012, Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes, Cancer Res source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“CXCL9/10/11 are ligands of the CXCR3 receptor involved in increased trafficking of CD8+CXCR3+ T cells to tumors (47,48,64).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [47] House, 2020, Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade, Clin Cancer Res source
- Not checked yetcites [48] Tokunaga, 2018, CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - a target for novel cancer therapy, Cancer Treat Rev source
- Not checked yetcites [64] Chow, 2019, Intratumoral activity of the cxcr3 chemokine system is required for the efficacy of anti-PD-1 therapy, Immunity source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, if a certain threshold of exercise intensity is not achieved, one should not expect mobilization and redistribution of antitumor cells.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr increases CD8+ T cells by reprogramming the TME towards a less aggressive phenotype, but a large fraction of CD8+ T cells remain expressing immune checkpoint receptors, suggesting these tumors would benefit from ICB therapy.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our findings support ExTr as a safer strategy to stimulate the antitumor CXCL9/11-CXCR3 system in solid tumors.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data indicate that, supervised ExTr has the potential to unleash antitumor response from immunotherapy in the clinic.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“ICB has revolutionized the treatment of multiple malignancies. However, its efficacy in BC has been modest (27,70).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 36
- Probably not a substantial claim. 21
- The quote only partly states this claim. 2
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“ICB mitigates CD8+ T-cell exhaustion by targeting these receptors and is approved for a subset of triple-negative BC patients (27).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Partly supportedcites [27] Zhang, 2020, Immunotherapeutic strategies in breast cancer: a clinical update, J Surg Oncol sourceExperimental — accuracy not yet measured
The “Checkpoint blockade in breast cancer” section says that PD-1/PD-L1 signaling inhibits T-cell effector functions and that checkpoint blockade aims to restore antitumor immunity. The Conclusions state that atezolizumab with nab-paclitaxel was approved for first-line treatment of PD-L1-positive metastatic triple-negative breast cancer. Our copy does not specifically say that blockade lessens CD8+ T-cell exhaustion. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Both CD8+ T-cell infiltration and IFNγ signaling signatures are indicative of benefit from combined anti-PD-1 and anti-CTLA-4 in patients with solid tumors (71) or anti-PD-L1 alone in BC (72).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Partly supportedcites [71] Grasso, 2020, Conserved interferon-gamma signaling drives clinical response to immune checkpoint blockade therapy in melanoma, Cancer Cell sourceExperimental — accuracy not yet measured
The Results section reports that CD8 T-cell infiltration predicts response to checkpoint blockade in advanced melanoma, and that responders’ biopsies had higher interferon-γ response-gene expression. The study included patients receiving combined anti-PD-1/anti-CTLA-4 therapy, but its findings concern melanoma and analyses that also include anti-PD-1 alone; they do not establish the stated prediction across solid tumors. The breast-cancer anti-PD-L1 clause is attached to a separate citation, so it is not assessed against this source. Page numbers are unavailable in our copy. (LLM, conf=0.87)
- Partly supportedcites [72] Sceneay, 2019, Interferon signaling is diminished with age and is associated with immune checkpoint blockade efficacy in triple-negative breast cancer, Cancer Discov sourceExperimental — accuracy not yet measured
The Results (page unavailable) link IFN-response signatures and CD8+ T-cell activity to response to single-agent anti-PD-L1 in mouse models of triple-negative breast cancer. The Discussion (page unavailable) suggests IFN-related genes may help identify patients for checkpoint-blockade monotherapy, but the paper does not establish that both CD8+ infiltration and IFNγ signatures predict benefit from anti-PD-L1 alone in breast cancer patients. The combined anti-PD-1/anti-CTLA-4 claim is attached to citation 71, not this source. (LLM, conf=0.84)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ExTr increased perfusion, alleviated hypoxia, and enhanced the infiltration of CD8+ T cells in the TME.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr improves immune checkpoint blockade therapy in BC
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We also determined cellular CXCL9 expression and found several CXCL9-expressing cell populations (Supplementary Fig. S10A-J).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We did not see any changes in other cell populations potentially relevant to antitumor immunity (Supplementary Fig. S7), such as tumor-associated macrophages (TAMs, CD45+Ly6G−Ly6ClowCD11b+F4/80+), DCs (CD45+Ly6G−CD11blowCD11c+), or natural killer cells (NK, CD45+TCRβ−NK1.1+).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr increases the infiltration of CD8+ T cells into BC TME
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Majority of the CD8+ T cells expressed IFNγ+, and there was no difference between groups (Fig. 6J).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using this clinically relevant ExTr protocol, we found that aerobic ExTr decreases tumor growth and reprograms the TME by increasing perfusion and decreasing hypoxia in established orthotopic BC models.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the other hand, the addition of ICB to ExTr exhibited superior BC tumor control, delaying tumor growth, reducing the final tumor volume, and further enhancing the antitumor effect of ExTr (Fig. 7B-C, Supplementary Fig. S11).”
- Also stated in: § ExTr improves immune checkpoint blockade therapy in BC · boosted
“Altogether, we demonstrated that ExTr intervention in established tumors normalized blood vessels, increased CD8+ T-cell infiltration, and improved control of refractory BC tumors when combined with ICB.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr improves immune checkpoint blockade therapy in BC
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § ExTr improves immune checkpoint blockade therapy in BC · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the other hand, no significant changes in conventional CD4+ (TCR+CD4+FOXP3−) or regulatory T cells (TCR+CD4+FOXP3+) were found (Fig. 4A).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr increases the infiltration of CD8+ T cells into BC TME
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, we could not identify a particular cell type that dominantly elevated CXCL9 expression with ExTr.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Consistent with previous preclinical reports (6,7), we showed that ExTr induces vessel normalization, characterized by a larger number of vessels with higher pericyte coverage, resulting in less tumoral hypoxia.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [6] Betof, 2015, Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise, J Natl Cancer Inst source
- Not checked yetcites [7] Schadler, 2016, Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy, Oncotarget source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Nevertheless, we found a transcriptional TME reprogramming in patients consistent with improved antitumor immunity and vessel normalization, similar to what we observed in preclinical models of BC.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [38] Ligibel, 2019, Impact of a pre-operative exercise intervention on breast cancer proliferation and gene expression: results from the Pre-Operative Health and Body (PreHAB) Study, Clin Cancer Res source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that ExTr modulated antitumor immune responses in preclinical models, as well as a transcriptional signature, consistent with the metabolic switch towards OXPHOS metabolism.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“To understand mechanisms promoting enhanced CD8+ T cell trafficking, we found ExTr increases the concentration of the chemokines CXCL9 and CXCL11, but not CXCL10, in breast tumors.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that controlled ExTr can facilitate immune cell Infiltration into tumors and sensitize them to ICB.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Among TILs, CD8+ T cells predict overall treatment response and overall survival in patients with BC (23-25).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [23] Liu, 2017, Role of cytotoxic tumor-infiltrating lymphocytes in predicting outcomes in metastatic HER2-positive breast cancer: a secondary analysis of a randomized clinical trial, JAMA Oncol source
- Not checked yetcites [24] Wang, 2017, The CD4/CD8 ratio of tumor-infiltrating lymphocytes at the tumor-host interface has prognostic value in triple negative breast cancer, Hum Pathol source
- Not checked yetcites [25] Savas, 2018, Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis, Nat Med source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“More importantly, a normalized tumor vasculature and microenvironment reprograms the immunosuppressive TME and enhances antitumor immunity (15).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [15] Huang, 2012, Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy, Proc Natl Acad Sci U S A source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Because the tumor vasculature is immature (12) and lacks myogenic and autonomic regulation (5)”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [12] Jain, 2005, Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy, Science source
- Not checked yetcites [5] McCullough, 2014, Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise, J Natl Cancer Inst source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Beyond the acute increase in perfusion, exercise training (ExTr, accumulated bouts of exercise sessions) induces vessel normalization, thus enhancing tumor blood flow and oxygenation in subsequent resting conditions as well (6,7).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Introduction
What the sources say
- Not checked yetcites [6] Betof, 2015, Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise, J Natl Cancer Inst source
- Not checked yetcites [7] Schadler, 2016, Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy, Oncotarget source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This molecular reprogramming suggests a less glycolytic and less immunosuppressive tumor, which is consistent with vessel normalization.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr reprograms the transcriptional signature of the TME
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“These cells were tested and authenticated (morphology check by microscopy, and antibodies for common viral contaminations, VRL Diagnostics, USA). The cell lines were also tested negative for mycoplasma.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Materials and Methods > Breast cancer cell lines.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We trained mice with the same relative exercise intensity (Supplementary Fig. S1D, ~60% of maximal running velocity).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr delays tumor growth in established BCs
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“When tumors reached ~100 mm3, mice were randomized to control (sedentary) or ExTr groups (Fig. 1A).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr delays tumor growth in established BCs
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“First, a Fragment Analyzer (Advanced Analytical Technologies Inc.) confirmed the quality of RNA samples (RIN 7.9-10).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Materials and Methods > Bulk RNA-seq analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results indicate that ExTr can improve antitumor immune activity and vessel normalization in not only mice, but also human BC patients.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > ExTr reprograms the transcriptional signature of the TME
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In voluntary running models conducted in the prevention setting (i.e., starting ad libitum run before implantation or appearance of tumors), NK cells (8) and CD8+ T cells (10) were previously reported to explain the antitumor effect of ExTr.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [8] Pedersen, 2016, Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution, Cell Metab source
- Not checked yetcites [10] Rundqvist, 2020, Cytotoxic T-cells mediate exercise-induced reductions in tumor growth, Elife source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For this analysis, tumors were time-matched and size-matched to avoid potential confounding factors.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Materials and Methods > Bulk RNA-seq analysis.
plainn = 5- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“It is well established that both NK and CD8+ T cells increase in the peripheral blood in response to acute exercise (58).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [58] Campbell, 2009, Acute exercise mobilises CD8+ T lymphocytes exhibiting an effector-memory phenotype, Brain Behav Immun source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No viability dyes were used.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Materials and Methods > Flow cytometry analysis.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All FVB mice completed the study.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Materials and Methods > Exercise testing and prescription.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Unbiased image quantification was conducted using custom software designed in MATLAB (Mathworks, USA).”
- Also stated in: § Histological image analysis. · plain
“a threshold value of at least μ+4σ was used.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Materials and Methods > Histological image analysis.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
- Also stated in: § Histological image analysis. · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Compliance was accessed by the percentage of completion of the prescribed ExTr program. We excluded mice that did not reach at least 75% of prescribed ExTr after randomization, representing ~20% of C57BL/6 mice.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Materials and Methods > Exercise testing and prescription.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Before starting the study, the cells were expanded and frozen in single vials (containing 106 cells in 50% FBS / 10% DMSO, Sigma-Aldrich, USA), so vials from the same batch would be thawed anytime we started a new mice cohort.”
- Also stated in: § Breast cancer cell lines. · plain
“Aliquots were thawed and implanted in mice after 3 (no more than 5) passages within 5-7 days.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Materials and Methods > Breast cancer cell lines.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § Breast cancer cell lines. · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These chemokines are induced by IFNγ and were potentially triggered in response to the ExTr-mediated increase of IFNγ-producing effector CD8+ T cells, thereby inducing positive feedback to attract more CD8+ T cells to tumors.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CXCL11 is not functional in C57BL/6 mice, so it was only quantified in the MCa-M3C tumor model in FVB mice (48).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [48] Tokunaga, 2018, CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - a target for novel cancer therapy, Cancer Treat Rev source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“There is an association of IFNγ-secreting T cells and vessel normalization (18), and IFNγ promotes the enhanced expression of adhesion molecules in endothelial cells (65).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This occurs as a function of exercise-induced adrenergic activation (8,59), linked to exercise intensity.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [8] Pedersen, 2016, Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution, Cell Metab source
- Not checked yetcites [59] Graff, 2018, beta2-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans, Brain Behav Immun source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“For example, Schadler et al. (7) showed increased perfusion in subcutaneous tumors in C57BL/6 mice by ExTr at 12 m/min.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [7] Schadler, 2016, Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy, Oncotarget source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Although vessel normalization can be observed with low-intensity ExTr (7), a higher exercise dose may be required for mobilization and redistribution of immune cells (8,58,59).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [7] Schadler, 2016, Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy, Oncotarget source
- Not checked yetcites [8] Pedersen, 2016, Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution, Cell Metab source
- Not checked yetcites [58] Campbell, 2009, Acute exercise mobilises CD8+ T lymphocytes exhibiting an effector-memory phenotype, Brain Behav Immun source
- Not checked yetcites [59] Graff, 2018, beta2-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans, Brain Behav Immun source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Data suggest that CXCR3 is not essential for the early recruitment of CD8+ T cells into tumors (64).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [64] Chow, 2019, Intratumoral activity of the cxcr3 chemokine system is required for the efficacy of anti-PD-1 therapy, Immunity source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Also, CD8+ T cells cannot compete with cancer cells for the scarce intratumoral glucose availability, which further impairs CD8+ T cells’ density and activity (61).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [61] Chang, 2015, Metabolic competition in the tumor microenvironment is a driver of cancer progression, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The relevance of the CXCL9/10/11-CXCR3 pathway for recruiting and triggering cytotoxic T cells is well known (47-50,64).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [47] House, 2020, Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade, Clin Cancer Res source
- Not checked yetcites [48] Tokunaga, 2018, CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - a target for novel cancer therapy, Cancer Treat Rev source
- Not checked yetcites [49] Moon, 2018, Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines, Oncoimmunology source
- Not checked yetcites [50] Luo, 2019, Cisplatin facilitates radiation-induced abscopal effects in conjunction with PD-1 checkpoint blockade through CXCR3/CXCL10-mediated T-cell recruitment, Clin Cancer Res source
- Not checked yetcites [64] Chow, 2019, Intratumoral activity of the cxcr3 chemokine system is required for the efficacy of anti-PD-1 therapy, Immunity source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“These cells display a strong affinity to CD8+CXCR3+ T cells (66), further increasing their infiltration.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [66] Curbishley, 2005, CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow, Am J Pathol source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Therefore, by inducing vessel normalization and promoting a less hypoxic tumor, ExTr allows a more favorable metabolic TME to facilitate the trafficking of T cells and trigger antitumor effector function (63).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [63] Weninger, 2001, Migratory properties of naive, effector, and memory CD8(+) T cells, J Exp Med source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“However, CXCR3 in CD8+ T cells is necessary to trigger initial effector responses in bystander CD8+ T cells (67), although not required for sustained IFNγ effector responses (68).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [67] Maurice, 2019, CXCR3 enables recruitment and site-specific bystander activation of memory CD8(+) T cells, Nat Commun source
- Not checked yetcites [68] Hu, 2011, Expression of chemokine receptor CXCR3 on T cells affects the balance between effector and memory CD8 T-cell generation, Proc Natl Acad Sci U S A source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Conversely, increased glycolytic rate and low perfusion/oxygenation contribute to intratumoral hypoxia and acidosis, which is alleviated with enhanced perfusion (12).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [12] Jain, 2005, Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Vessel normalization may occur at ExTr intensities lower than that employed in our study.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Their ligands are reported to function both as biomarkers and inducers of response to anti-PD-1 alone (64) or in combination with anti-CTLA-4 (47).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [64] Chow, 2019, Intratumoral activity of the cxcr3 chemokine system is required for the efficacy of anti-PD-1 therapy, Immunity source
- Not checked yetcites [47] House, 2020, Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade, Clin Cancer Res source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Tumors are predominantly glycolytic and with low glucose in the TME of aggressive tumors (61).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [61] Chang, 2015, Metabolic competition in the tumor microenvironment is a driver of cancer progression, Cell source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hence, transient mobilization of immune cells might occur in response to every exercise session, thus favoring re-localization and immune surveillance of tumors.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Lack of perfusion, tumoral hypoxia, and T-cell exclusion are considered significant resistance mechanisms (15,17-19).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [15] Huang, 2012, Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy, Proc Natl Acad Sci U S A source
- Not checked yetcites [17] Zheng, 2018, Increased vessel perfusion predicts the efficacy of immune checkpoint blockade, J Clin Invest source
- Not checked yetcites [18] Tian, 2017, Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming, Nature source
- Not checked yetcites [19] Schmittnaegel, 2017, Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade, Sci Transl Med source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Several therapeutic approaches have been tested to leverage this pathway to attract more CD8+ T cells, including radiation, chemotherapy (50), and vaccination (49).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [50] Luo, 2019, Cisplatin facilitates radiation-induced abscopal effects in conjunction with PD-1 checkpoint blockade through CXCR3/CXCL10-mediated T-cell recruitment, Clin Cancer Res source
- Not checked yetcites [49] Moon, 2018, Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines, Oncoimmunology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Multimodal therapy increases ICB response, but it is associated with increased adverse events (69).”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Discussion
What the sources say
- Not checked yetcites [69] Martins, 2019, Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance, Nat Rev Clin Oncol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The way exercise changes host immune responses against cancer, alone or with immune modulators, remains incompletely understood.
“However, how exercise modulates host immune responses against cancer or in combination with immune modulators is not fully understood.”
The paper relies on this without support.
An abnormal tumor microenvironment caused partly by poor perfusion excludes CD8+ T cells and reduces the effect of immunotherapies such as immune checkpoint blockade.
“An abnormal TME, caused in part by hypoperfusion, results in the exclusion of CD8+ T cells and reduces the impact of immunotherapies such as ICB.”
The paper relies on this without support.
C57BL/6 mice do not express functional CXCL11.
“C57BL/6 mice do not express functional CXCL11.”
The paper relies on this without support.
No prior report has described exercise training's ability to improve immunotherapy in established tumors.
“ExTr is an emerging antitumor strategy (2,10), yet its potential to enhance immunotherapy in established tumors has not been reported.”
The authors state this as an assumption.
A single exercise training velocity is suitable for every mouse strain and experimental condition.
“We found a significant variability of ExTr dose within preclinical models, even though it is usually assumed that the same ExTr velocity would fit all mouse strains and experimental conditions.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Exercise restrains tumor growth5 and enhances immune checkpoint inhibitor (ICI) efficacy in various preclinical cancer models8–13”
From Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy (2025) · cites this paper as [10]
In the citing paper
“Exercise exerts potent antitumor effects in both preclinical models5,8–13 and cancer patients6.”
From Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy (2025) · cites this paper as [10]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Abstract
“The recruitment of CD8+ T cells and the antitumor effects of ExTr were abrogated in Cxcr3−/− mice, supporting the causal role of the CXCL9/CXCL11-CXCR3 pathway.”
§ Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade > Results > CXCL9/11-CXCR3 pathway mediates the antitumor effect of ExTr
“ExTr induced a small but significant increase in CD8+ T cells in Cxcr3-KO mice, suggesting CXCR3-independent mechanisms of CD8+ T-cell recruitment (Fig. 6H–I).”
Citations
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709
World Health Organization 2020 guidelines on physical activity and sedentary behaviour
Bull, F. C., Al-Ansari, S. S., Biddle, S., Borodulin, K., Buman, M. P., Cardon, G., Carty, C., Chaput, J.-P., Chastin, S., Chou, R., et al. (2020) · British Journal of Sports Medicine · doi:10.1136/bjsports-2020-102955 · Cited by 11,657
Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy
Jain, R. K. (2005) · Science · doi:10.1126/science.1104819 · Cited by 5,527 · cited 2×
“Conversely, increased glycolytic rate and low perfusion/oxygenation contribute to intratumoral hypoxia and acidosis, which is alleviated with enhanced perfusion (12).”
BackgroundSelf-citationSoftware for Computing and Annotating Genomic Ranges
Lawrence, M. F., Huber, W. K., Pagès, H., Aboyoun, P., Carlson, M. R. J., Gentleman, R. C., Morgan, M. T., & Carey, V. J. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003118 · Cited by 4,475
Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
Chang, C.-H., Qiu, J., O’Sullivan, D., Buck, M. D., Noguchi, T., Curtis, J. D., Chen, Q., Gindin, M., Gubin, M. M., van der Windt, G. J. W., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.016 · Cited by 3,331
Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance
Martins, F., Sofiya, L., Sykiotis, G. P., Lamine, F., Maillard, M., Fraga, M., Shabafrouz, K., Ribi, C., Cairoli, A., Guex-Crosier, Y., et al. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0218-0 · Cited by 2,314
Enrichment Map: A Network-Based Method for Gene-Set Enrichment Visualization and Interpretation
Merico, D., Isserlin, R., Stueker, O., Emili, A., & Bader, G. D. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013984 · Cited by 2,235
Denkert, C., von Minckwitz, G., Darb-Esfahani, S., Lederer, B., Heppner, B. I., Weber, K. E., Budczies, J., Huober, J., Klauschen, F., Furlanetto, J., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(17)30904-x · Cited by 2,157
Research works printed but not linked: 3
- Liu, 2017, Role of cytotoxic tumor-infiltrating lymphocytes in predicting outcomes in metastatic HER2-positive breast cancer: a secondary analysis of a randomized clinical trial, JAMA Oncol, 3, e172085, 10.1001/jamaoncol.2017.2085 · DOI · Paper page
- American College of Sports Medicine, 2018, ACSM's guidelines for exercise testing and prescription
- Chen, 2013, Role of macrophage polarization in tumor angiogenesis and vessel normalization: implications for new anticancer therapies, Int Rev Cell Mol Biol, 301, 1
Cited by
Sorted by citations
Kurz, E., Hirsch, C. A., Dalton, T., Shadaloey, S. A., Khodadadi-Jamayran, A., Miller, G., Pareek, S., Rajaei, H., Mohindroo, C., Baydogan, S., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.05.006 · Cited by 258
Immune determinants of the pre-metastatic niche
Pătraș, L., Shaashua, L., Matei, I. R., & Lyden, D. C. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.018 · Cited by 229
The effect of physical exercise on anticancer immunity
Fiuza‐Luces, C., Valenzuela, P. L., Gálvez, B. G., Ramírez, M. R., López‐Soto, A., Simpson, R. J., & Lucía, A. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00943-0 · Cited by 164
“For example, a higher alpha diversity with a high abundance of Faecalibacterium has been associated with enhanced systemic and local antitumour immunity, mediated through increased antigen presentation and improved effector T cell function in the blood and the tumour microenvironment 96 .”
Targeting inflammation as cancer therapy
Wang, M., Chen, S., He, X., Yuan, Y., & Wei, X. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01528-7 · Cited by 126
“…of agents targeting the upstream factors or receptors of MDSC accumulation are being tested to potentiate ICB efficacy, it has to be addressed that the majority of MDSC-recruiting chemokines can also act on other immune cells with anti-tumor activities such as T lymphocytes [95] and NK cells [96].”
BackgroundRole of chemokine systems in cancer and inflammatory diseases
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Metadata
- Authors
- Gomes-Santos, I. L., Amoozgar, Z., Kumar, A. S., Ho, W. W., Roh, K., Talele, N. P., Curtis, H., Kawaguchi, K., Jain, R. K., & Fukumura, D.
- Affiliations
- Harvard University (US)
- Corresponding author
- Jain, Rakesh K.
- Fukumura, Dai
- ORCID
- Venue
- Cancer Immunology Research
- Published
- 2021-04-10
- Volume
- 9
- Issue
- 7
- Pages
- 765-778
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC8295193
- OpenAlex
- W3153058261
- Cited by
- 181
- References
- 74
- Citations by year
- 2026: 46 · 2025: 34 · 2024: 42 · 2023: 27 · 2022: 29 · 2021: 2
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2014/13690–8, #2016/21320–1)
- NCI (#R25CA174650)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Keywords
- exercise training, breast cancer, CD8+ T cells, CXCR3, tumor microenvironment, immune checkpoint blockade, anti-PD-1, anti-CTLA-4, tumor vasculature normalization, pericytes, tumor hypoxia, immunotherapy sensitization, antitumor immunity
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Breast Neoplasms, Combined Modality Therapy, Disease Models, Animal, Exercise Therapy, Female, Humans, Physical Conditioning, Animal, Signal Transduction, Mice, Knockout, CD8-Positive T-Lymphocytes, Drug Resistance, Neoplasm, Cell Line, Tumor, Mice, Receptors, CXCR3, Chemokine CXCL9, Chemokine CXCL11, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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