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.
- 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
“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.
- 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
“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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“These recent studies further demonstrated that significantly enriched B cells localized in TLS, specifically switched memory B cells (99), are key predictors of ICI response.”
BackgroundTertiary lymphoid structures in cancer – considerations for patient prognosis
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“Multiple memory B cell phenotypes have been detected in TLSs. 6 Such as IgG1 + memory B lymphocytes were enriched in pancreatic cancer, showing a positive correlation with TLS density.”
BackgroundInfluentialRefining colorectal cancer classification and clinical stratification through a single-cell atlas
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“Recently, two studies have described a major role of B cells in melanoma and soft-tissue sarcomas inmediating responses to immunotherapy; however, the role of B cells in HNSCC, and the effect of specific treatment regimens, including PD-1 blockade and radiotherapy, on modulating B-cell populations remains largely unkn…”
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“found that B-cell biomarkers were differentially expressed in tumors of immune responders and nonresponders, indicating that B cells and their products may play a critical role in the antitumor immune response([27]).”
BackgroundSelf-citationTargeting the tumour vasculature: from vessel destruction to promotion
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“Thereby, TU-HEV density, concomitant with the magnitude of TLSs, exhibited prolonged metastasis-free, relapse-free or OS rates and has been predictive of response to ICB in soft-tissue sarcomas, renal cell carcinomas and melanomas 296,297 .”
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“Furthermore, Helmink et al. 235 leveraged CyTOF and single-cell sequencing to reveal a distinctive B cell functional status and tertiary lymphoid structure localization in a melanoma neoadjuvant ICB clinical trial cohort.”
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“Three key gene-expression studies published last year highlighted the importance of TLS and TIL-B in predicting responses to immunotherapy and survival in patients with sarcoma (12), melanoma (10, 11), and renal cell carcinoma (11).”
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“Modern multiplex imaging technologies are emerging as an improved modality to study these structures as evident in several recent publications (73, 77, 82).”
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“IHC analysis Tumors were harvested at the indicated times, and immunostaining was performed on tissue sections using standard methodology, scanned and analyzed as described earlier (31).”
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“TLS are considered to aggravate the in fl ammatory response in autoimmune disease such as multiple sclerosis (MS) 21 , while in several types of cancer they are associated with improved response to immunotherapy and a favorable prognosis 22 – 26 .”
Barriers to immune cell infiltration in tumors
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T resident helper cells promote humoral responses in the lung
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“Recently, the potential role of B cells within tertiary lymphoid structures in the response to ICIs was also reported in patients with melanoma and renal cell carcinoma [30].”
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“Nevertheless, B cells could be of additional relevance considering recent studies on the role of B cells for response to checkpoint blockade [27].”
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“Notably, three seminal studies recently published by Nature comprehensively described the importance of TLS in the context of ICB (2, 4, 30).”
BackgroundInfluentialCancer Immunoediting in the Era of Immuno-oncology
Gubin, M. M., & Vesely, M. D. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-1804 · Cited by 167
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“Hence, therapeutic induction of TLS could be a way to boost responses to ICIs, although experimental induction of TLS using either CD40 agonists or the chemokines CXCL13 and CCL21 in preclinical models have thus far yielded mixed results 137,138 , suggesting that more knowledge is required to enable targeting of TLS i…”
InfluentialTertiary lymphoid structures and B lymphocytes in cancer prognosis and response to immunotherapies
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Nongenetic Evolution Drives Lung Adenocarcinoma Spatial Heterogeneity and Progression
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“Two runs of highly-multiplexed and spatially-resolved proteomic profiling of tumor and immune 774 cells were performed with the GeoMx Digital Spatial Profiler (NanoString) as previously described 775 (52) on 5 (batch1) and 3 (batch2) FFPE tissue sections.”
BackgroundMethodLocalization, tissue biology and T cell state — implications for cancer immunotherapy
Schenkel, J. M., & Pauken, K. E. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00884-8 · Cited by 144
Interpretable systems biomarkers predict response to immune-checkpoint inhibitors
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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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