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.
- 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
“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.
- 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
“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.
- 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
“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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- 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
“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.
- 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
“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.
- 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
“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.
- 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 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.
- 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
“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
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Cited by
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Self-citationTGFβ control of immune responses in cancer: a holistic immuno-oncology perspective
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“in the tertiary lymphoid structures in human tumors as a strong prognostic factor for a favorable response to immunotherapy.(74,78,79) Moreover, an ICOSL B cell subset emerges in tumors after chemotherapy to elicit antitumor immunity.”
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“145,146 Spatial profiling has enabled detailed characterization of TLS distribution, maturation states, and functional roles.”
Self-citationSong, W., Ren, J., Xiang, R., Kong, C., & Fu, T. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1987636 · Cited by 133
“reported that the levels of the B cell-related genes MZB1, JCHAIN, and IGLL5 were markedly higher in patients who responded to immune checkpoint blockade compared to those in non-responders.(35) Moreover, tumor-infiltrating B cells were associated with a favorable prognosis in CRC.”
ResultDongye, Z., Li, J., & Wu, Y. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-01876-6 · Cited by 138
“In addition, circulating anti-tumour antibodies and tumourassociated tertiary lymphoid structures can significantly affect the clinical efficacy and prognosis of cancer patients, which means that B cells also play an important role in anti-tumour immunity [51].”
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“They found a higher expression of biomarkers of T-cell activation in TLS-associated T cells (64).”
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“Their presence is associated with a good prognosis and response to immunotherapy and may activate antitumor immune responses [20–23].”
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“Across multiple tumour types, B cells contribute to anti-tumour immunity 35–37 , likely through both antibody-dependent and antibody-independent mechanisms.”
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“TLS has been shown to modulate anti-tumor immune 346 activity and be associated with immunotherapy response [35-37].”
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Self-citationImmune-checkpoint inhibitor resistance in cancer treatment: Current progress and future directions
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“These might explain the positive associations of higher TLS presentation with a higher degree of tumour-in fi ltrating immune cells 24 , favourable patient survival, and better responses to immune checkpoint blockade (ICB) therapy in multiple human tumours 23,25,26 .”
Ovarian cancer-derived IL-4 promotes immunotherapy resistance
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PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes
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Spatial analysis with SPIAT and spaSim to characterize and simulate tissue microenvironments
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“Intratumoural tertiary lymphoid structures (TLS) have been linked with improved outcomes across many cancer types 137–139 , including ovarian cancer 140–142 , reflecting their biologically relevant role in antitumour immunity 143 .”
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“The presence of tertiary lymphoid structures with the TME enhances the immune response to ICIs 90–92 .”
Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?
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Standardized Pathology Screening of Mature Tertiary Lymphoid Structures in Cancers
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Self-citationRegulatory T cells in the tumour microenvironment
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“In humans, tumour-associated TLSs are more prevalent in responders than non-responders to ICI therapy 89–91 .”
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“Researchers [67] also reported that B cells could suppress tumors by activating immune effector cells or producing antibodies.”
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“To address the contribution of the heterogeneous cell composition of the tumors and relate it to the gene expression patterns detected previously, we used the algorithm MCP counter, which is based on the detection of cell type-specific mRNA [18, 19, 24].”
MethodLeveraging self-assembled nanobiomaterials for improved cancer immunotherapy
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“Until now, clinical practices and strategies are focused on primary immune escape and maximizing the immune response of the T‐cell compartment, however, only a few studies have investigated on secondary immune escape or other immune subtypes in response to ICB treatment.(10) Moreover, some patients with melanoma, urot…”
MethodRoles and mechanisms of tumour-infiltrating B cells in human cancer: a new force in immunotherapy
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“Melanoma B cells 136 CD20 Peritumoral TLS Better response to ICIs [75]”
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Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer
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Beneficial autoimmunity improves cancer prognosis
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“Checkpoint inhibition can induce proliferation of the CD21IgD B-cell population, resulting in increased percentages of CD21 B cells in tumor samples of patients with melanoma (1, 44).”
BackgroundCombined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
Tang, K. H., Li, S., Khodadadi-Jamayran, A., Jen, J., Han, H., Guidry, K., Chen, T., Hao, Y., Fedele, C., Zebala, J. A., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0369 · Cited by 105
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“13 14 Our previous study demonstrated that intratumor T cells were positive associated with a good prognosis of CRCLMs. 3 Mean-while, several studies have focused on the significance of tertiary lymphoid structures (TLSs), an analog of secondary lymphoid organs, which are classically defined as…”
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The Benefits and Safety of Monoclonal Antibodies: Implications for Cancer Immunotherapy
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“122,123”
Self-citationMolecular Features of Cancers Exhibiting Exceptional Responses to Treatment
Wheeler, D. A., Takebe, N., Hinoue, T., Hoadley, K. A., Cardenas, M., Hamilton, A. M., Laird, P. W., Wang, L., Johnson, A., Dewal, N., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.10.015 · Cited by 103
“Of note, emerging studies have associated therapeutic response with increased abundance of tumor-infiltrating B cells and/or activated NK cells (Cabrita et al., 2020; Helmink et al., 2020; Hollern et al., 2019; Muntasell et al., 2019; Petitprez et al., 2020).”
BackgroundSelf-citationKašíková, L., Raková, J., Hensler, M., Láníčková, T., Tománková, J., Pasulka, J., Drozenová, J., Mojžíšová, K., Fialová, A., Vosahlikova, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46873-w · Cited by 111
“This is particularly relevant as TMB has recently been shown to predict superior ICI responsiveness in patients that receive conventional ICIs such a NSCLC 58 , and the same holds true for intratumoral TLS abundance and frequency of T FH cells 22,23,25,26 .”
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“The presence of B cells and/or TA-TLS prior to treatment is associated with favorable responses to checkpoint blockade immunotherapies in melanoma (14, 47, 48) and soft-tissue sarcoma (49), and one of these studies presents evidence suggesting that immunotherapy might increase TLS density (47).”
BackgroundHighly multiplexed tissue imaging using repeated oligonucleotide exchange reaction
Kennedy‐Darling, J., Bhate, S. S., Hickey, J. W., Black, S., Barlow, G. L., Vazquez, G., Venkataraaman, V. G., Samusik, N., Goltsev, Y., Schürch, C. M., et al. (2021) · European Journal of Immunology · doi:10.1002/eji.202048891 · Cited by 108
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High Endothelial Venules: A Vascular Perspective on Tertiary Lymphoid Structures in Cancer
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“For instance, TU-HEVs can be present in T cell- and DC-rich areas (74, 91) while also present in B cell-rich areas (92, 93).”
BackgroundGaudreau, P.-O., Negrao, M. V., Mitchell, K. G., Reuben, A., Corsini, E. M., Li, J., Karpinets, T. V., Wang, Q., Diao, L., Wang, J., et al. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.09.027 · Cited by 102
Self-citationCrosstalk between angiogenesis and immune regulation in the tumor microenvironment
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Convergent inducers and effectors of T cell paralysis in the tumour microenvironment
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Cancer vaccines: current status and future directions
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“B cell responses within the tumor microenvironment (TME) promote anti-tumor immunity and enhance sensitivity to ICIs [64].”
Harris, R. J. C., Cheung, A., Ng, J. C.-F., Laddach, R., Chenoweth, A. M., Crescioli, S., Fittall, M. W., Dominguez-Rodriguez, D., Roberts, J., Levi, D., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3773 · Cited by 100
The immune cell atlas of human neuroblastoma
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“Three studies demonstrated that B cells and the presence of TLSs in adult tumors correlated with improved response to immunotherapy in melanoma and sarcoma.(51,80,81) In human NB, a paper on the interaction between dendritic cells and NK cells detected the presence of TLSs.”
BackgroundResultDeciphering Tumor Ecosystems at Super-Resolution from Spatial Transcriptomics with Tesla
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“Although immune checkpoint inhibitors (ICIs) have drastically altered the landscape of oncology therapy by interfering with cancer cell–T-cell interactions and overcoming tumor tolerance, recent evidence suggests that B cells have a potential role in response to these therapies (143).”
BackgroundBergholtz, H., Carter, J. M., Cesano, A., Cheang, M. C. U., Church, S., Divakar, P., Fuhrman, C. A., Goel, S., Gong, J., Guerriero, J. L., et al. (2021) · Cancers · doi:10.3390/cancers13174456 · Cited by 101
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PTEN loss correlates with T cell exclusion across human cancers
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“The presence of TLS is not only associated with improved clinical outcome in multiple cancers, but also found to promote immunotherapy response in patients with melanoma or renal cell carcinoma [33, 34].”
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“S8) consistent with prior findings linking such structures with improved CPI outcomes (30, 31).”
BackgroundSelf-citationEpigenetic state determines the in vivo efficacy of STING agonist therapy
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Regulatory B cells and T cell Regulation in Cancer
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T follicular helper and B cell crosstalk in tertiary lymphoid structures and cancer immunotherapy
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“Indeed, ICB efficacy is highly dependent of the constitution of the tumor cell immunogenicity, the host immune recognition and, ultimately, the TiME (Bonaventura et al., 2019).”
BackgroundInfluential
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
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 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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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