The DOI matches its Crossref record; 66 of the 66 references it cites were found in a registry or an index; none of the 11 sources its claims cite is checked for support yet.
B cells and tertiary lymphoid structures promote immunotherapy response
Open accessAbstract
Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers 1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity 11-15, although these have been less well-studied in ICB treatment 16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling 17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter 18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
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48 Own result · 19 Own method · 11 Own interpretation · 9 Not checked yet
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In the paper
“Moreover, these findings were corroborated in translational studies of separate cohorts of patients with melanoma36 and sarcoma37 who were treated with ICB.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
What the sources say
- Not checked yetcites [36] Cabrita, R. L. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature https://doi.org/10.1038/s41586-019-1914-8 (2020). source
- Not checked yetcites [37] Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature https://doi.org/10.1038/s41586-019-1906-8 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“B cells were not significantly associated with pathological response rates in an analogous trial of neoadjuvant-targeted therapy in patients with BRAF-mutated melanoma38”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
What the sources say
- Not checked yetcites [38] Amaria, R. N. et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 19, 181–193 (2018). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Findings of high B cell lineage scores in responders were replicated in samples from an additional cohort of patients with melanoma treated with neoadjuvant versus adjuvant checkpoint blockade (ClinicalTrials.gov identifier NCT02437279, OpACIN-neo trial) (n = 12 responders, 6 non-responders)35”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
What the sources say
- Not checked yetcites [35] Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018). source
plaincorrelationaln = 12- Asserted: passes — The authors put it forward as true.
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In the paper
“B cell signatures alone were predictive of response in univariable analyses (odds ratio 2.6, P = 0.02 for our trial, and odds ratio 2.9, P = 0.03 for combined melanoma cohorts)”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“but not in multivariable analyses when considering other components of the immune cell infiltrate”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In these analyses, we again observed enrichment of a B cell signature in responders versus non-responders at baseline and early on-treatment (P = 0.036 and 0.038, respectively).”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Gene expression profiling by microarray and subsequent MCP-counter analysis of baseline tumour samples was performed, demonstrating significantly higher expression of B-cell-related genes in responders versus non-responders (P = 0.0011, n = 17 responders and 11 non-responders)”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Similar B cell signature observed in RCC
boostedcorrelationaln = 17- Asserted: passes — The authors put it forward as true.
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In the paper
“Other genes that are expected to alter the function of B cells were also significantly enriched in responders versus non-responders, such as FCRL5, IDO1, IFNG and BTLA.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders.”
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
“TLSs are associated with markers of T cell activation and response and B cell proliferation.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 23
- Probably not a substantial claim. 28
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
“significantly higher expression of B-cell-related genes such as MZB1, JCHAIN and IGLL5 was observed in patients that respond to ICB treatment versus non-responding patients (‘responders’ and ‘non-responders’, hereafter) at baseline (P < 0.001) with over-representation of these genes compared to T cells and other immune markers (with evaluable tumours from seven responders and nine non-responders)”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Importantly, there was no clear association of MICs with known genomic subtypes of melanoma (BRAF, NRAS, NF1 or triple wild type)42 or disease site (nodal or non-nodal)”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells prognostic in TCGA analysis
What the sources say
- Not checked yetcites [42] Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015). source
plainn = 136- 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
“Pathway analysis was also performed on bulk RNA-seq data from our clinical trial cohort, revealing increased immune signalling pathways in responders than in non-responders, including T cell receptor signalling, major histocompatibility complex-mediated antigen presentation and processing, differentiation of T helper 1 and 2 (TH1 and TH2) cells, and costimulatory signalling associated with T cell”
§ B cells and tertiary lymphoid structures promote immunotherapy response > BCR and single-cell RNA-seq offer functional insight
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
“For tumour, this included 9 responders and 9 non-responders, and for peripheral blood mononuclear cells, 8 responders and 8 non-responders.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Sample preparation and acquisition
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Similar analyses were performed to assess the expression of immune-related genes in clear-cell RCC from the TCGA (TCGA-KIRC, n = 526)43. In these analyses, similar immune classes were observed; however, immune infiltration was not associated with survival in these patients (P = 0.24)”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells prognostic in TCGA analysis
What the sources say
- Not checked yetcites [43] Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013). source
plainn = 526- 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
“yielding a final stage III TCGA-SKCM cohort of n = 136.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > TCGA SKCM and KIRC data downloading and patient selection
plainn = 136- Asserted: passes — The authors put it forward as true.
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In the paper
“resulting in a median of approximately 1.4 million paired-end reads and a median of 2,588 genes detected per cell.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Single-cell sequencing and analysis of CD45+ B cells
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. 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
“The density of CD20+ B cells and TLSs, and the ratio of TLSs to tumour area were higher in responders than in non-responders in our neoadjuvant melanoma cohort, particularly in early on-treatment samples (P = 0.0008, P = 0.001 and P = 0.002, respectively), although statistical significance was not reached for all the markers in the baseline samples (P = 0.132, P = 0.078 and P = 0.037, respectively”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells localized in the context of TLSs
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 identified significantly increased clonal counts for both immunoglobulin heavy and light chains (IgH and IgL; P = 0.001 and P = 0.004, respectively) and increased BCR diversity in responders than in non-responders (P = 0.002 and P = 0.0008)”
§ B cells and tertiary lymphoid structures promote immunotherapy response > BCR and single-cell RNA-seq offer functional insight
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Other notable differences included an increase in plasma cells in responders compared with non-responders; however, this did not reach significance and was largely driven by data from one patient (P = 0.3)”
§ B cells and tertiary lymphoid structures promote immunotherapy response > CyTOF shows differential B cell phenotypes
plaincorrelationalSingle case- 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
“For TCGA-KIRC, the cases without available expression data were excluded and a total of 526 cases were taken into subsequent analysis.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > TCGA SKCM and KIRC data downloading and patient selection
plainn = 526- Asserted: passes — The authors put it forward as true.
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In the paper
“No significant differences were identified when testing for associations of each individual cluster (G1–G4) with the clinical outcome, probably owing to limited sample size.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > BCR and single-cell RNA-seq offer functional insight
hedged- 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
“Analogous immunohistochemical findings were observed in our cohort of patients with RCC treated with pre-surgical ICB, with increased infiltration of CD20+ cells and TLSs density associated with response to treatment (Extended Data Fig. 6b–d); these TLSs are morphologically similar to those found in melanoma”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells localized in the context of TLSs
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“TLSs are associated with response in RCC similar to those observed in melanoma.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
plaincorrelationaln = 10- Asserted: passes — The authors put it forward as true.
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In the paper
“tumours from responders had a significantly higher frequency of memory B cells, whereas non-responders had a significantly higher frequency of naive B cells (P = 0.033 for naive and P = 0.033 for memory)”
§ B cells and tertiary lymphoid structures promote immunotherapy response > CyTOF shows differential B cell phenotypes
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“As in the case of melanoma, B cell signatures were predictive of a response in univariable analysis in the RCC cohort (odds ratio 61.2, P = 0.05) but not multivariable analysis”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Similar B cell signature observed in RCC
plaincorrelationaln = 17- Asserted: passes — The authors put it forward as true.
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In the paper
“Survival data were missing for 9 of 136 samples, so n = 127 samples were available for overall survival analyses.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > TCGA SKCM and KIRC data downloading and patient selection
plainn = 127- Asserted: passes — The authors put it forward as true.
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In the paper
“we found that B cells were significantly enriched in tumours from responders versus non-responders and were predictive of a response (odds ratio 1.05, P = 0.02)”
§ B cells and tertiary lymphoid structures promote immunotherapy response > BCR and single-cell RNA-seq offer functional insight
What the sources say
- Not checked yetcites [44] Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013 (2018). source
plaincorrelationaln = 48- Asserted: passes — The authors put it forward as true.
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In the paper
“This process yielded a median robustness measure of 0.96 for the selected k=11.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Unsupervised clustering of immune cells
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“There are 28 available pre-treatment samples from 3 arms: nivolumab (n = 6), nivolumab plus bevacizumab (n = 14) and nivolumab plus ipilimumab (n = 8).”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Affymetrix microarray for RCC
plainn = 28- Asserted: passes — The authors put it forward as true.
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In the paper
“architectural analysis showed that CD20+ B cells were localized in TLSs of tumours of responders, and were colocalized with CD4+, CD8+and FOXP3+ T cells.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells localized in the context of TLSs
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“which suggests that B cells probably act together with other immune subsets and are not acting in isolation”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“however, B cells have previously been shown to be positively associated with responses to chemotherapy in other cancer types39,40.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells found in the tumours of responders
What the sources say
- Not checked yetcites [39] Reddy, S. M. et al. Poor response to neoadjuvant chemotherapy correlates with mast cell infiltration in inflammatory breast cancer. Cancer Immunol. Res. 7, 1025–1035 (2019). source
- Not checked yetcites [40] Song, I. H. et al. Predictive value of tertiary lymphoid structures assessed by high endothelial venule counts in the neoadjuvant setting of triple-negative breast cancer. Cancer Res. Treat. 49, 399–407 (2017). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“however, sample size was again limited”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Similar B cell signature observed in RCC
plainn = 17- Asserted: passes — The authors put it forward as true.
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In the paper
“No statistical methods were used to predetermine sample size.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Statistical analyses
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The correlation matrix was carefully reviewed and the sequencing event generated from one library pool that showed poor correlation with other library pools from the same RNA sample were removed before sample-level merging of BAM files.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > RNA-seq data processing and quality check
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In the paper
“Samples with fewer than 200 CD45+CD19+ B cells were not used for downstream analyses.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Data analysis
plain- 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
“The observation of switched memory B cells (that can differentiate into plasma cells) in responders suggests that they could be potentially contributing to the anti-tumour response by producing antibodies against the tumours.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Summary
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Switched memory B cells can differentiate into plasma cells.
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
“Representative transmission electron micrographs showing Dynabead with exosomes present after immunocapture.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“for each patient, we collected and sequenced the same number of cells (n = 384 CD45+ cells per plate). Thus, the number of cells per patient is equal”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Single-cell sequencing and analysis of CD45+ B cells
plain- 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
“RNA quality was assessed on an Agilent 2100 Bioanalyzer using the Agilent RNA 6000 Nano Chip with smear analysis to determine DV200 and original RNA concentration.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Gene expression profiling and analysis: RNA extraction for neoadjuvant melanoma ICB-treated cohort
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. 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
“Technical replicates were constrained to n = 1 per time point, owing to limited tissue availability in patient-derived samples as well as prioritization for multiple studies.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Statistical analyses
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.
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
“Nanoimager-captured images of the beads coated with CD63+ exosomes as compared with isotype control.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
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.
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
“Protein targets with a signal to noise ratio less than 2 were removed from downstream analysis.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > nCounter hybridization assay for photocleaved oligo counting
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.
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
“Five random areas on each sample were analysed blindly by a pathologist at 20× magnification.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Multiplex immunofluorescence assay and 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
“Only in-frame productive clonotypes were taken into subsequent analysis.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > B cell clonotype analyses
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
“These data represent combined tumour and peripheral blood samples from patients with melanoma treated with ICB ran together (8 tumour n = 5 R and n = 3 NR and 8 peripheral blood samples n = 4 R and n = 4 NR), thus eliminating batch effect.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
plaindirectn = 8- 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
“The experiments were not randomized”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Statistical analyses
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
“For one sample, the Nanosight measurement was erroneous and excluded. All samples were included in the flow cytometric analyses.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Flow cytometric analyses of exosomes
plainSingle case- 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. 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
“The reads that had ≥ 15 contiguous low-quality bases (phred score < 20) were removed from the FASTQ files.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > RNA-seq data processing and quality check
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
“investigators were not blinded to allocation during experiments and outcome assessment unless stated otherwise.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Statistical analyses
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
“We identify similar mature TLSs in patients with extra-nodal metastases (Extended Data Fig. 5b), which suggests that TLSs may develop in non-nodal sites and are associated with the response to ICB treatment.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells localized in the context of TLSs
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.
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
“Responder versus non-responder status was blinded until flow cytometry data capture and FlowJo analyses were completed.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Flow cytometric analyses of exosomes
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 paper relies on this without support.
B cells can secrete cytokines including TNF, IL-2, IL-6, and IFNγ, and through these cytokines activate and recruit other immune effector cells including T cells.
“B cells can also secrete an array of cytokines (including TNF, IL-2, IL-6 and IFNγ), through which they activate and recruit other immune effector cells, including T cells.”
The paper relies on this without support.
Switched memory B cells can differentiate into plasma cells.
“switched memory B cells (that can differentiate into plasma cells)”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Also, as a member of the 12-chemokine gene signature classifier33, its expression has been correlated with the presence of tumor-associated tertiary lymphoid structures50–52 which are rapidly emerging as a powerful prognostic marker in melanoma and a number of other cancer types53–55.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [54]
Experimental — accuracy not yet measuredIn the citing paper
“Tertiary lymphoid structures (TLS) have recently emerged as biomarkers of response to ICT across several tumor types, including lung cancer, melanoma, RCC, sarcoma, and urothelial cancer (163-167).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [164]
In the citing paper
“Presence of B cells in tumor was associated with a better response to neoadjuvant therapy with ICB in melanoma and renal cell carcinoma (Cabrita et al., 2020; Helmink et al., 2020).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Helmink et al., 2020
In the citing paper
“Tumor-infiltrating B cell populations in responder tumors were enriched in memory B cells; in contrast, naïve B cells were more prominent in non-responder tumors (Helmink et al., 2020).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Helmink et al., 2020
In the citing paper
“Mounting evidence on the role of the gut and tumor microbiome, stress, and diet in tumor immunity and response to ICB (Helmink et al., 2020) has created a foundation for emerging adjunct therapies.”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Helmink et al., 2020
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
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
“Figure: Extended Data Fig. 4 | Immune infiltrate is prognostic of improved diseasespecific survival in TCGA cutaneous melanoma cohort but not the clear-cell RCC cohort.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
“b, Kaplan–Meier estimates of overall survival of MIC groups. c, Kaplan–Meier estimates of overall survival by B cell lineage scores shown by high and low groups dichotomized by median values.”
Citations
Cites
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InfluentialSTAR: ultrafast universal RNA-seq aligner
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Influentiallimma powers differential expression analyses for RNA-sequencing and microarray studies
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PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
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“Significant progress has been made in this regard, with the identification of several validated biomarkers, particularly for immune checkpoint blockade (ICB) 1-10 .”
Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients
Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., Karpinets, T. V., Prieto, P. A., Vicente, D., Hoffman, K., Wei, S. C., et al. (2018) · Science · doi:10.1126/science.aan4236 · Cited by 4,812
Self-citationCytoscape 2.8: new features for data integration and network visualization
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IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade
Ayers, M., Lunceford, J., Nebozhyn, M., Murphy, E., Loboda, A., Kaufman, D. R., Albright, A., Cheng, J. D., Kang, S. P., Shankaran, V., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci91190 · Cited by 3,788
Cited by
Sorted by citations
Items 601–700 of 1,004
Tertiary lymphoid structures and B lymphocytes: a promising therapeutic strategy to fight cancer
Esparcia-Pinedo, L., Romero-Laorden, N., & Alfranca, A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1231315 · Cited by 40
“Furthermore, cancer patients who responded to PD-1 and/or CTLA4 blockade had a higher basal number of TLSs with increased B-cell densities than non-responders (5, 7, 115, 116).”
BackgroundNakamura, S., Ohuchida, K., Hayashi, M., Katayama, N., Tsutsumi, C., Yamada, Y., Hisano, K., Okuda, S., Ohtsubo, Y., Iwamoto, C., et al. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02396-7 · Cited by 41
“The clinicopathological characteristics of patients are listed in Supplementary Table S1.”
NSCLC: from tumorigenesis, immune checkpoint misuse to current and future targeted therapy
Kafkova, L. R., Mierzwicka, J. M., Chakraborty, P., Jakubec, P., Fischer, O., Škarda, J., Malý, P., & Raška, M. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1342086 · Cited by 46
“Previous studies have established the TLSs as predictive biomarkers for the ef fi cacy of immunotherapy in sarcoma, melanoma, and renal cell carcinoma (76, 77).”
Wortzel, I., Seo, Y., Akano, I., Shaashua, L., Tobias, G. C., Hebert, J. M., Kim, K., Kim, D., Dror, S., Liu, Y., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00862-6 · Cited by 43
Rosario, S. R., Long, M. D., Chilakapati, S. R., Gomez, E. C., Battaglia, S., Singh, P. K., Wang, J., Wang, K., Attwood, K. M., Hess, S. M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54565-8 · Cited by 40
“Furthermore, the absence of B cells and tertiary lymphoid structures (TLS) is linked to poor survival rates and diminished response to ICB 9,10 .”
Self-citationA comparative view on the expression patterns of PD-L1 and PD-1 in soft tissue sarcomas
Orth, M. F., Bücklein, V., Kampmann, E., Subklewe, M. S., Noeßner, E., Cidre‐Aranaz, F., Romero‐Pérez, L., Wehweck, F. S., Lindner, L. H., Issels, R. D., et al. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02552-5 · Cited by 41
Relecom, A., Merhi, M., Inchakalody, V. P., Shahab Uddin, M. S., Rinchai, D., Bedognetti, D., & Dermime, S. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01872-3 · Cited by 41
“Several studies report TLSassociated gene-expression signatures in tumors at baseline to be predictive of longer overall survival in patients treated with PD-1 and/or CTLA-4 blockade [150, 160, 161].”
BackgroundYan, X., Xie, Y., Yang, F., Hua, Y., Zeng, T., Sun, C., Yang, M., Huang, X., Wu, H., Fu, Z., et al. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01949-z · Cited by 41
“vestigation is needed to uncover the underlying mechanisms [127, 134].”
BackgroundSTINGing the Tumor Microenvironment to Promote Therapeutic Tertiary Lymphoid Structure Development
Filderman, J. N., Appleman, M., Chelvanambi, M., Taylor, J. L., & Storkus, W. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.690105 · Cited by 42
“non-responders, and these mature TLS appeared more secondary-follicle-like and contained CD21 follicular DC and CD23 germinal center B cells (79).”
BackgroundFarlow, J. L., Brenner, J. C., Lei, Y. L., & Chinn, S. B. (2021) · Oral Oncology · doi:10.1016/j.oraloncology.2021.105420 · Cited by 41
“These formations lack capsules and thus experience direct antigenic stimulation and have been associated with a robust immune response and more favorable prognosis in multiple malignancies [42, 43].”
BackgroundNeoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer
Peyrottes, A., Ouzaïd, I., Califano, G., Hermieu, J., & Xylinas, E. N. (2021) · Medicina · doi:10.3390/medicina57080769 · Cited by 40
“Given that B-cell activity and tertiary lymphoid structures improve immunotherapy in melanoma, these two biomarkers have been tested in bladder cancer [13,14].”
BackgroundJohannet, P. M., Liu, W., Fenyö, D., Wind‐Rotolo, M., Krogsgaard, M., Mehnert, J. M., Weber, J. S., Zhong, J., & Osman, I. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-0404 · Cited by 40
“There is increasing recognition that the B-cell compartment impacts ICB response, but the role of antibody-mediated immunity has not been fully elucidated (26, 27).”
BackgroundSelf-citationBiomarkers for immune checkpoint inhibition in sarcomas – are we close to clinical implementation?
Yiong, C. S., Lin, T. P., Lim, V., Toh, T. B., & Yang, V. S. (2023) · Biomarker Research · doi:10.1186/s40364-023-00513-5 · Cited by 42
“TLS have been found to benefit prognosis [204–207] and are also associated with favorable ICI treatment outcomes [127, 204, 208–211] in several cancers.”
BackgroundEngineered Cancer Nanovaccines: A New Frontier in Cancer Therapy
Wang, Y., Liu, C., Fang, C., Peng, Q., Qin, W., Yan, X., & Zhang, K. (2024) · Nano-Micro Letters · doi:10.1007/s40820-024-01533-y · Cited by 41
The 12-CK Score: Global Measurement of Tertiary Lymphoid Structures
Li, R., Berglund, A., Zemp, L., Dhillon, J., Putney, R., Kim, Y., Jain, R. K., Grass, G. D., Conejo-Garcia, J., & Mulé, J. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.694079 · Cited by 39
“Cabrita et al. constructed a signature using hallmark TLSrelated genes (CCL19, CCL21,CXCL13, CCR7, CXCR5, SELL and LAMP3) (14), while Helmink et al. resorted to B cell related genes (MZB1, JCHAIN, IGLL5, FCRL5, IDO1, IFNG and BTLA) (15).”
BackgroundInfluentialFeng, H., Yang, F., Qiao, L., Zhou, K., Wang, J., Zhang, J., Tian, T., Du, Y., & Shangguan, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.693234 · Cited by 39
“gov/aboutdata/publications/panimmune) (11).”
ResultB cells in pancreatic cancer stroma
Delvecchio, F. R., Goulart, M. R., Fincham, R. E. A., Bombadieri, M., & Kocher, H. M. (2022) · World Journal of Gastroenterology · doi:10.3748/wjg.v28.i11.1088 · Cited by 40
Jiang, A., Meng, J., Bao, Y., Wang, A., Gong, W., Gan, X., Wang, J., Bao, Y., Wu, Z., Lü, J., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.755212 · Cited by 37
“Meanwhile, with the in-depth study of tumor infiltrating B cells and the concept of TLS, a new direction is provided for tumor immunotherapy (28).”
BackgroundSelf-citationWu, J., Hou, L., Haoran, E., Zhao, Y., Yu, X., Xu, L., Ye, N., Deng, J., Sun, K., Zhang, J., et al. (2022) · Lung Cancer · doi:10.1016/j.lungcan.2022.01.019 · Cited by 39
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Microenvironmental network of clonal CXCL13+CD4+ T cells and Tregs in pemphigus chronic blisters
Han, D., Lee, A., Kim, T., Choi, J. Y., Cho, M. Y., Song, A., Kim, C.-H., Shim, J., Kim, H. J., Kim, H., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci166357 · Cited by 39
Modugno, F. D., Carlo, A. D., Spada, S., Palermo, B., D’Ambrosio, L., D’Andrea, D., Morello, G., Belmonte, B., Sperduti, I., Balzano, V., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105003 · Cited by 39
Self-citationWeng, Y., Yuan, J., Cui, X., Wang, J., Chen, H., Li, X., Chen, X., Peng, M., & Song, Q. (2024) · Scientific Reports · doi:10.1038/s41598-024-64980-y · Cited by 40
LTβR Agonism Promotes Antitumor Immune Responses via Modulation of the Tumor Microenvironment
An, D., Chen, G., Cheng, W., Mohrs, K., Adler, C., Gupta, N. T., Atwal, G. S., DiLillo, D. J., Daly, C., Lin, J. C., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-2716 · Cited by 41
Oncolytic immunotherapy with nivolumab in muscle-invasive bladder cancer: a phase 1b trial
Li, R., Villa, N., Yu, X., Johnson, J., Borjas, G. J., Dhillon, J., Segura, C. M., Kim, Y., Francis, N. L., Dorman, D., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03324-9 · Cited by 42
Peripheral blood immune cell-based biomarkers in anti-PD-1/PD-L1 therapy
Kim, K. H., Kim, C. G., & Shin, E. (2020) · Immune Network · doi:10.4110/in.2020.20.e8 · Cited by 37
“Recently, B cells and presence of tertiary lymphoid structures in tumor tissue have also been suggested as predictors of response to immune checkpoint blockade (22-24).”
BackgroundSadeghirad, H., Bazaz, S. R., Monkman, J. H., Warkiani, M. E., Rezaei, N., O'Byrne, K. J., & Kulasinghe, A. (2020) · Clinical & Translational Immunology · doi:10.1002/cti2.1215 · Cited by 37
“In the responders, CD20 B cells were located in TLSs of tumors and were colocalised with CD4, CD8 and FoxP3 T cells.(59)”
BackgroundLiu, J., Liu, Q., Zhang, X., Cui, M., Li, T., Zhang, Y., & Liao, Q. (2021) · Cancer Cell International · doi:10.1186/s12935-021-01824-z · Cited by 39
Remodeling of Stromal Cells and Immune Landscape in Microenvironment During Tumor Progression
Arora, L., & Pal, D. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.596798 · Cited by 39
Herck, Y. V., Antoranz, A., Andhari, M. D., Milli, G., Bechter, O. E., Smet, F. D., & Bosisio, F. M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.636681 · Cited by 40
“As discussed earlier, the use of multiplex immunofluorescence confirmed the importance of tumor-associated B cells and TLS in metastatic melanoma (42, 43), a finding that was further corroborated by spatial transcriptomics, indicating that T cells in TLS-negative tumors had a dysfunctional molecular phenotype (42) whe…”
BackgroundMethodResultSchaafsma, E., Jiang, C., & Cheng, C. (2021) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2021.72 · Cited by 40
Zhang, L., Li, Y., Dai, Y., Wang, D., Wang, X., Cao, Y., Liu, W., & Tao, Z. (2021) · Scientific Reports · doi:10.1038/s41598-021-98381-2 · Cited by 38
Self-citationAbdulrahman, Z., Santegoets, S. J. A. M., Sturm, G., Charoentong, P., Ijsselsteijn, M. E., Somarakis, A., Höllt, T., Finotello, F., Trajanoski, Z., van Egmond, S. L., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004346 · Cited by 38
Freeman, S. S., Sade-Feldman, M., Kim, J., Stewart, C., Gonye, A. L. K., Ravi, A., Arniella, M. B., Gushterova, I., LaSalle, T. J., Blaum, E. M., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100500 · Cited by 41
Self-citationSpatial determinants of CD8+ T cell differentiation in cancer
Tooley, K., Escobar, G., & Anderson, A. C. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.04.003 · Cited by 38
Emerging concepts regarding pro- and anti tumor properties of B cells in tumor immunity
Qin, Y., Lu, F., Lyu, K., Chang, A. E., & Li, Q. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.881427 · Cited by 40
“Once entering the GCs, most of B cells display the proliferation marker Ki67, activation-induced deaminase (AID) as well as transcription factor BCL-6 (6–8, 19).”
BackgroundInfluentialDying tumor cells-inspired vaccine for boosting humoral and cellular immunity against cancer
Qin, X., Yang, T., Xu, H., Zhang, R., Zhao, S., Kong, L., Yang, C., & Zhang, Z. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.05.044 · Cited by 37
Zhou, W., Kawashima, S., Ishino, T., Kawase, K., Ueda, Y., Yamashita, K., Watanabe, T., Kawazu, M., Dansako, H., Suzuki, Y., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113797 · Cited by 38
The potential and promise for clinical application of adoptive T cell therapy in cancer
Li, Y., Zheng, Y., Liu, T., Liao, C., Shen, G., & He, Z. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05206-7 · Cited by 41
“The prognostic value of TLSs has been demonstrated among the various types of cancer [44–46].”
BackgroundCha, J., Kim, D., Kim, G., Cho, J.-W., Sung, E., Baek, S., Hong, M. H., Kim, C. G., Sim, N. S., Hong, H. J., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-008667 · Cited by 42
“Evidence of CD161 as a co-inhibitory receptor molecule requires further validation in virus-induced cancer before it is accepted as a novel and effective immuno-therapy target.”
Self-citationWang, Y., Zhang, G., Zhang, X., Liu, G., Zhang, L., Chen, L., Sang, S., Yao, S., Fei, Y., Tian, Z., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-65421-8 · Cited by 41
Alessandrini, L., Franz, L., Ottaviano, G., Ghi, M. G., Lanza, C., Blandamura, S., & Marioni, G. (2020) · Oral Oncology · doi:10.1016/j.oraloncology.2020.104836 · Cited by 37
Wang, S., Yuan, P., Mao, B., Li, N., Ying, J., Tao, X., Tang, W., Zhang, L., Geng, X., Zhang, F., et al. (2022) · npj Precision Oncology · doi:10.1038/s41698-021-00244-6 · Cited by 38
Emergence of the CD226 Axis in Cancer Immunotherapy
Conner, M., Hance, K. W., Yadavilli, S., Smothers, J. F., & Waight, J. D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.914406 · Cited by 42
Neoadjuvant Immunotherapy in Melanoma: The Paradigm Shift
Hieken, T. J., Kreidieh, F., Aedo-Lopez, V., Block, M. S., McArthur, G. A., & Amaria, R. N. (2023) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_390614 · Cited by 37
Self-citationWu, Y., Zhao, J., Wang, Z., Liu, D., Tian, C., Ye, B., Sun, Y., Li, H., & Wang, X. (2023) · International Journal of Surgery · doi:10.1097/js9.0000000000000741 · Cited by 40
“Previous studies have demonstrated the in fl uence of immunotherapy on systemic immunity [56,57] , as well as its ability to modulate the formation and function of TLS in various cancer types [16,40 – 42, 58, 59 ] .”
Yuan, H., Mao, X., Yan, Y., Huang, R., Zhang, Q., Zeng, Y., Bao, M., Dai, Y., Fang, B., Mi, J., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-04860-1 · Cited by 37
“Previous studies have demonstrated an enrichment of proliferative B cells in both TLSs and tumors responsive to immunotherapy, highlighting the potential relevance of TLS formation and activity in certain tumor [13, 16].”
BackgroundMethodResultInfluentialWang, J., Liang, Y., Ao, X., Xiao, J., Zhao, X., Cao, S., Li, P., Dong, J., Li, Y., Xu, Z., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009603 · Cited by 36
Block, M. S., Clubb, J. H. A., Maenpaa, J. U., Pakola, S. A., Quixabeira, D. C. A., Kudling, T. V., Jirovec, E., Haybout, L., van der Heijden, M., Zahraoui, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56482-w · Cited by 36
“Accumulating evidence demonstrates that a proportion of high-grade serous ovarian cancer (HGSOC) are T cell in fl amed, suggesting their suitability for immunotherapy 2 .”
InfluentialCell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy
Coleman, M. F., Cozzo, A. J., Pfeil, A. J., Etigunta, S. K., & Hursting, S. D. (2020) · Cancers · doi:10.3390/cancers12040852 · Cited by 37
“The formation of tertiary lymphoid structures within the TME is an emerging marker of ICI response in renal cell carcinoma and melanoma [97,98].”
BackgroundRyan, S. T., Zhang, J., Burner, D., Liss, M. A., Pittman, E. I., Muldong, M., Shabaik, A. S., Woo, J. R., Bassler, N., Cunha, J., et al. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02370-4 · Cited by 37
Circular RNA and tumor microenvironment
Song, H., Liu, Q., & Liao, Q. (2020) · Cancer Cell International · doi:10.1186/s12935-020-01301-z · Cited by 37
Liu, J., Li, Y., Li, Q., Liang, D., Wang, Q., & Liu, Q. (2021) · Breast Cancer Research and Treatment · doi:10.1007/s10549-021-06128-4 · Cited by 36
Tertiary Lymphoid Structures in the Central Nervous System: Implications for Glioblastoma
van de Walle, T., Vaccaro, A., Ramachandran, M., Pietilä, I., Essand, M., & Dimberg, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.724739 · Cited by 38
“TLS are present in many types of solid tumors and are generally associated with positive prognosis and improved response to immunotherapy (42, 47, 48).”
BackgroundNeoadjuvant therapy for melanoma: rationale for neoadjuvant therapy and pivotal clinical trials
Witt, R. G., Erstad, D. J., & Wargo, J. A. (2022) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359221083052 · Cited by 35
Self-citationPeripheral Helper T Cell Responses in Human Diseases
Yoshitomi, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.946786 · Cited by 35
Yang, X., Gao, M., Xu, R., Tao, Y., Wang, L., Wang, B., Zhong, W., He, L., & He, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.969447 · Cited by 36
“In addition, some studies have shown that the expression of B cell-related genes, such as MZB1, JCHAIN and IGLL5, is significantly increased in patients who respond to ICI therapy, suggesting the potential of B cells in improving anti-tumor immune response (8).”
ResultSelf-citationVallet, N., Grand, S. L., Bondeelle, L., Hoareau‐Coudert, B., Corneau, A., Bouteiller, D., Tournier, S., Lew‐Derivry, L., Bohineust, A., Tourret, M., et al. (2022) · Blood · doi:10.1182/blood.2022016926 · Cited by 37
Spatial Deconvolution of HER2-positive Breast Tumors Reveals Novel Intercellular RelationshipsPreprint
Andersson, A., Larsson, L., Stenbeck, L., Salmén, F., Ehinger, A., Wu, S. Z., Al‐Eryani, G., Roden, D. L., Swarbrick, A., Borg, Å., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.14.200600 · Cited by 36
“[45] Having deconvolved the cell type composition of each spot, we were able to identify which spots that exhibited a high degree of co-localization between B and T-cells, ergo potentially constituting parts of a TLS-site.”
BackgroundRefining patient selection for breast cancer immunotherapy: beyond PD-L1
Kossai, M., Radosevic-Robin, N., & Penault-Llorca, F. (2021) · ESMO Open · doi:10.1016/j.esmoop.2021.100257 · Cited by 36
“B cells and TLS seem to facilitate response to ICIs as shown in recent publications on melanoma and sarcoma.(114,116,120)”
BackgroundJammihal, T., Saliby, R. M., Labaki, C., Soulati, H., Gallegos, J., Peris, A., McCurry, D., Yu, C., Shah, V., Poduval, D., et al. (2025) · Nature Cancer · doi:10.1038/s43018-024-00896-w · Cited by 38
“…evidence linking the humoral adaptive response and, more specifically, TLS entities to improved outcomes to immunotherapy across multiple tumor types 33 , with an enrichment of B cell signatures among responders to ICIs in melanoma and RCC and a localization of B cells within TLS formations 33 .”
Nayar, S., Pontarini, E., Campos, J., Berardicurti, O., Smith, C. G., Asam, S., Gardner, D. H., Colafrancesco, S., Lucchesi, D., Coleby, R., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03344-6 · Cited by 35
Single-Cell Analysis in Immuno-Oncology
Christodoulou, M., & Zaravinos, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098422 · Cited by 35
Immunometabolic reprogramming, another cancer hallmark
Kumar, V., & Stewart, J. H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1125874 · Cited by 37
Khanal, S., Wieland, A., & Gunderson, A. J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1267654 · Cited by 35
Liu, Y., Altreuter, J., Bodapati, S., Cristea, S., Wong, C. J., Wu, C. J., & Michor, F. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100444 · Cited by 39
“20 Furthermore, responders had a correlated higher expression of B cell markers in pre-treatment and treatment samples.”
BackgroundMethodLow-dose radiotherapy promotes the formation of tertiary lymphoid structures in lung adenocarcinoma
Wang, D., Huang, L., Qian, D., Cao, Y., Wu, X., Xu, P., Liang, M., Tang, J., Huang, Z., Yin, Y., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1334408 · Cited by 35
“Recently, numerous reports have shown that TLSs can enhance the response to immune checkpoint inhibitors (ICIs) treatment (13, 14).”
BackgroundLee, H., Park, S., Yun, J. H., Seo, C., Ahn, J. M., Cha, H., Shin, Y. S., Park, H. R., Lee, D., Roh, J., et al. (2024) · Journal of Medical Virology · doi:10.1002/jmv.29386 · Cited by 36
“70,71 Several studies have revealed the presence of TLS in patients with HPV − HNSCC.”
BackgroundNerviani, A., Boutet, M., Ghirardi, G. M., Goldmann, K., Sciacca, E., Rivellese, F., Pontarini, E., Prediletto, E., Abatecola, F., Caliste, M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46564-6 · Cited by 42
The rising roles of exosomes in the tumor microenvironment reprogramming and cancer immunotherapy
Wu, Y., Han, W., Dong, H., Liu, X., & Su, X. (2024) · MedComm · doi:10.1002/mco2.541 · Cited by 36
“48 In clinical cohort studies, B cells from ICI responders were in clonal expansion and unique functional status, 49 and patients in the B cell-rich immune subgroup were more sensitive to anti-PD-1 treatment.”
BackgroundMaurer, K., Park, C. Y., Mani, S., Borji, M., Raths, F., Gouin, K. H., Penter, L., Jin, Y., Zhang, J. Y., Shin, C. S., et al. (2025) · Science Immunology · doi:10.1126/sciimmunol.adr0782 · Cited by 42
Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma
Galvani, E., Mundra, P. A., Valpione, S., García-Martínez, P. L., Smith, M., Greenall, J., Thakur, R., Helmink, B. A., Andrews, M. C., Boon, L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14632-2 · Cited by 36
Self-citationEpigenetic modulation of immunotherapy and implications in head and neck cancer
Zhou, L., Xu, N., Shibata, H., Saloura, V., & Uppaluri, R. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09944-0 · Cited by 36
Immunovirotherapy: The role of antibody based therapeutics combination with oncolytic viruses
Jafari, M., Kadkhodazadeh, M., Shapourabadi, M. B., Goradel, N. H., Shokrgozar, M. A., Arashkia, A., Abdoli, S., & Sharifzadeh, Z. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1012806 · Cited by 37
Clinical relevance of tertiary lymphoid structures in esophageal squamous cell carcinoma
Deguchi, S., Tanaka, H., Suzuki, S., Natsuki, S., Mori, T., Miki, Y., Yoshii, M., Tamura, T., Toyokawa, T., Lee, S., et al. (2022) · BMC Cancer · doi:10.1186/s12885-022-09777-w · Cited by 34
“performed RNA-seq of tissues from patients with melanoma and renal cell carcinoma who participated in clinical trials of immune checkpoint inhibition therapy and reported that the expressions of genes involved in changes in B cell function and TLS density were markedly increased in the treatment response group, and th…”
MethodMiheecheva, N., Postovalova, E., Lyu, Y., Ramachandran, A., Bagaev, A., Svekolkin, V., Galkin, I., Zyrin, V., Maximov, V., Lozinsky, Y., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111180 · Cited by 37
Neglected no more: B cell-mediated anti-tumor immunity
Conejo-Garcia, J. R., Biswas, S., Chaurio, R. A., & Rodrı́guez, P. C. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101707 · Cited by 35
Detection and quantitative analysis of tumor-associated tertiary lymphoid structures
Yang, M., Che, Y., Li, K., Fang, Z., Li, S., Wang, M., Zhang, Y., Zhu, X., Luo, L., Wu, C. K., et al. (2023) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2200605 · Cited by 34
Wang, Y., Bin, T., Tang, J. Y., Xu, X., Lin, C., Lü, B., & Sun, T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1268090 · Cited by 33
Hsiehchen, D., Beg, M. S., Kainthla, R., Lohrey, J., Kazmi, S. M. A., Khosama, L., Maxwell, M. C., Kline, H., Katz, C., Hassan, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46542-y · Cited by 34
Unveiling spatial complexity in solid tumor immune microenvironments through multiplexed imaging
Scheuermann, S., Kristmann, B., Engelmann, F., Nuernbergk, A., Scheuermann, D., Koloseus, M., Abed, T., Solaß, W., & Seitz, C. M. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1383932 · Cited by 36
Zheng, K. C., Hai, Y., Chen, H., Zhang, Y., Hu, X., & Ni, K. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05186-8 · Cited by 36
“Additionally, SIII represented reduced B cells and plasma cells, which would also undermine ICB efficacy [27, 77, 98].”
BackgroundNF2: An underestimated player in cancer metabolic reprogramming and tumor immunity
Xu, D., Yin, S., & Shu, Y. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00627-5 · Cited by 36
Sadeghirad, H., Monkman, J. H., Tan, C. W., Liu, N., Yunis, J., Donovan, M. L., Moradi, A., Jhaveri, N., Perry, C., Adams, M. N., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05409-y · Cited by 35
“Studies have highlighted the critical role of TLSs within the TME across various tumor types, implying their significance as primary sites for tumor antigen presentation [17, 18].”
Beyond the Driver Mutation: Immunotherapies in Gastrointestinal Stromal Tumors
Dugage, M. R., Jones, R. L., Trent, J. C., Champiat, S., & Dumont, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.715727 · Cited by 37
Li, X., Yang, Y., Huang, Q., Deng, Y., Guo, F., Wang, G., & Liu, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.738373 · Cited by 36
Zhao, H., Wang, H., Zhou, Q., & Ren, X. (2021) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2021.0029 · Cited by 36
Self-citationWang, X., Chang, S., Wang, T., Wu, R., Huang, Z., Sun, J., Liu, J., Yu, Y., & Mao, Y. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.857289 · Cited by 34
“It is suggested that infiltrating B lymphocytes play an important role in the treatment of ICB and predict the prognosis (Cabrita et al., 2020; Helmink et al., 2020; Petitprez et al., 2020).”
BackgroundTwo sides of the same coin: Protective versus pathogenic CD4 + resident memory T cells
Oja, A. E., van Lier, R. A. W., & Hombrink, P. (2022) · Science Immunology · doi:10.1126/sciimmunol.abf9393 · Cited by 35
Comprehensive Analysis of GLUT1 Immune Infiltrates and ceRNA Network in Human Esophageal Carcinoma
Liu, X., Gao, Y. P., Wu, L., Wan, H., Peng, Y., Yang, J., Guo, S., Wang, Y., Chen, X., Zhou, L.-M., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.665388 · Cited by 33
“(62) found that the number of memory B cells in immune responders increased greatly, and they played a role in inhibiting tumor cell proliferation and metastasis.”
BackgroundGu, S., Qian, L., Zhang, Y., Chen, K., Li, Y., Wang, J., & Wang, P. (2021) · Biochimica et biophysica acta. Reviews on cancer · doi:10.1016/j.bbcan.2021.188632 · Cited by 18
Bao, J., Betzler, A. C., Heß, J., & Brunner, C. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1233085 · Cited by 35
Jiao, R., Lin, X., Zhang, Q., Zhang, Y., Qin, W., Yang, Q., Xu, C. S., Chen, F., & Zhang, K. (2023) · Progress in Materials Science · doi:10.1016/j.pmatsci.2023.101230 · Cited by 34
Sun, Y., Chen, S., Lu, Y., Xu, Z., Fu, W., & Yan, W. (2024) · Communications Biology · doi:10.1038/s42003-024-05765-x · Cited by 33
“Analyses of the composition of immune cells in tumor tissues from metastatic melanoma and renal cell carcinoma cohorts have found that B cells and TLSs are positively correlated with patients ’ responses to immunotherapy 49 .”
Lymphatic system regulation of anti-cancer immunity and metastasis
Lei, P., Fraser, C. S., Jones, D., Ubellacker, J. M., & Padera, T. P. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1449291 · Cited by 39
Robust identification of perturbed cell types in single-cell RNA-seq data
Nicol, P. B., Paulson, D., Qian, G., Liu, X. S., Irizarry, R. A., & Sahu, A. D. (2024) · Nature Communications · doi:10.1038/s41467-024-51649-3 · Cited by 35
“Differential abundance approaches, such as DA-seq, Milo, and Meld (3; 4; 5; 6), focus on identifying cell types with varying proportions between conditions.”
MethodLong, S., Li, M., Chen, J., Zhong, L., Dai, G., Pan, D., Liu, W., Yi, F., Ruan, Y., Zou, B., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-011126 · Cited by 33
Self-citationHan, L., Shi, H., Luo, Y., Sun, W., Li, S., Zhang, N., Jiang, X., Gong, Y. Q., & Xie, C. (2020) · Cancer Medicine · doi:10.1002/cam4.3561 · Cited by 33
Inflammatory B cells correlate with failure to checkpoint blockade in melanoma patients
de Jonge, K., Tillé, L., Lourenço, J., Hajjami, H. M.-E., Nassiri, S., Racle, J., Gfeller, D., Delorenzi, M., Verdeil, G., Baumgaertner, P., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1873585 · Cited by 33
“The presence of TLS in different types of cancers is mostly described as a positive prognostic marker .(52) Recent evidence shows a positive role for B cells in the TLS and its association with response to ICB.”
Background
Metadata
- Authors
- Helmink, B. A., Reddy, S. M., Gao, J., Zhang, S., Basar, R., Thakur, R., Yizhak, K., Sade-Feldman, M., Blando, J., Han, G., Gopalakrishnan, V., Xi, Y., Zhao, H., Amaria, R. N., Tawbi, H. A., Cogdill, A. P., Liu, W., LeBleu, V. S., Kugeratski, F. G., Patel, S., Davies, M. A., Hwu, P., Lee, J. E., Gershenwald, J. E., Lucci, A., Arora, R., Woodman, S., Keung, E. Z., Gaudreau, P.-O., Reuben, A., Spencer, C. N., Burton, E. M., Haydu, L. E., Lazar, A. J., Zapassodi, R., Hudgens, C. W., Ledesma, D. A., Ong, S., Bailey, M., Warren, S., Rao, D., Krijgsman, O., Rozeman, E. A., Peeper, D., Blank, C. U., Schumacher, T. N., Butterfield, L. H., Zelazowska, M. A., McBride, K. M., Kalluri, R., Allison, J., Petitprez, F., Fridman, W. H., Sautès-Fridman, C., Hacohen, N., Rezvani, K., Sharma, P., Tetzlaff, M. T., Wang, L., & Wargo, J. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Massachusetts General Hospital (US)
- Broad Institute (US)
- Parker Institute for Cancer Immunotherapy (US)
- Nanostring Technologies (United States) (US)
- The Netherlands Cancer Institute (NL)
- University of Pittsburgh (US)
- Inserm (FR)
- Corresponding author
- Helmink, Beth A.
- Wargo, Jennifer A.
- ORCID
- Helmink, Beth A.
- Reddy, Sangeetha M.
- Gao, Jianjun
- Zhang, Shaojun
- Thakur, Rohit
- Yizhak, Keren
- Sade-Feldman, Moshe
- Blando, Jorge
- Han, Guangchun
- Gopalakrishnan, Vancheswaran
- Xi, Yuanxin
- Zhao, Hao
- Liu, Wenbin
- LeBleu, Valerie S.
- Kugeratski, Fernanda G.
- Patel, Sapna
- Davies, Michael A.
- Hwu, Patrick
- Lee, Jeffrey E.
- Gershenwald, Jeffrey E.
- Lucci, Anthony
- Arora, Reetakshi
- Woodman, Scott
- Keung, Emily Z.
- Gaudreau, Pierre-Olivier
- Reuben, Alexandre
- Spencer, Christine N.
- Burton, Elizabeth M.
- Haydu, Lauren E.
- Lazar, Alexander J.
- Hudgens, Courtney W.
- Rao, Disha
- Krijgsman, Oscar
- Rozeman, Elisa A.
- Peeper, Daniel
- Blank, Christian U.
- Schumacher, Ton N.
- Zelazowska, Monika A.
- McBride, Kevin M.
- Kalluri, Raghu
- Allison, James
- Petitprez, Florent
- Fridman, Wolf Herman
- Hacohen, Nir
- Rezvani, Katayoun
- Sharma, Padmanee
- Wang, Linghua
- Wargo, Jennifer A.
- Venue
- Nature
- Published
- 2020-01-15
- Volume
- 577
- Issue
- 7791
- Pages
- 549-555
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8762581
- OpenAlex
- W2998795792
- Cited by
- 2,731
- References
- 66
- Citations by year
- 2026: 422 · 2025: 422 · 2024: 458 · 2023: 393 · 2022: 433 · 2021: 383 · 2020: 217
- FWCI
- 129.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- AIM at Melanoma
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health (W81XWH, CA- 016672)
- University of Texas MD Anderson Cancer Center ((CA016672), T32 CA 009599, P30-CA-016672)
- National Cancer Institute (T32CA009666, R01CA213233, CA213233, R01CA195733, CA195733, P30CA008748, T32CA009599, P30CA016672, P01CA117969)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- B cells, tertiary lymphoid structures, immune checkpoint blockade, cancer immunotherapy response, melanoma, renal cell carcinoma, switched memory B cells, B cell clonal expansion, tumor immune microenvironment, predictive biomarkers, MCP-counter, tumor-infiltrating immune cells
- MeSH terms
- Tertiary Lymphoid Structures, RNA-Seq, B-Lymphocytes, Carcinoma, Renal Cell, Clone Cells, Humans, Immunologic Memory, Immunotherapy, Melanoma, Neoplasm Metastasis, Phenotype, Prognosis, Receptors, Immunologic, Mass Spectrometry, T-Lymphocytes, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Dendritic Cells, Follicular, Single-Cell Analysis, Cell Cycle Checkpoints, Transcriptome
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A second model labelled each claim on 2026-10-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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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