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.
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- 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.
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- 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 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.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- 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.
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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.
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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 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.
- It may state two separate claims as one. 36
- Probably not a substantial claim. 21
- The quote only partly states this claim. 2
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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.
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- Partly supported
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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.
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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
“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.
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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.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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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.
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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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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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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.
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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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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.
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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.
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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.
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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.
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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 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.
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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.
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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.
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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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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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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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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.
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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
“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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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.
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- 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.
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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.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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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
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“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 .”
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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.
What counts as a claim ›How we measure confidence ›How we check this ›
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