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.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Technical replicates were constrained to n = 1 per time point, owing to limited tissue availability in patient-derived samples as well as prioritization for multiple studies.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Statistical analyses
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Nanoimager-captured images of the beads coated with CD63+ exosomes as compared with isotype control.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Protein targets with a signal to noise ratio less than 2 were removed from downstream analysis.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > nCounter hybridization assay for photocleaved oligo counting
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Five random areas on each sample were analysed blindly by a pathologist at 20× magnification.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Multiplex immunofluorescence assay and analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Only in-frame productive clonotypes were taken into subsequent analysis.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > B cell clonotype analyses
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The experiments were not randomized”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Statistical analyses
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For one sample, the Nanosight measurement was erroneous and excluded. All samples were included in the flow cytometric analyses.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Flow cytometric analyses of exosomes
plainSingle case- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The reads that had ≥ 15 contiguous low-quality bases (phred score < 20) were removed from the FASTQ files.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > RNA-seq data processing and quality check
plain- Asserted: passes — The authors put it forward as true.
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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
“investigators were not blinded to allocation during experiments and outcome assessment unless stated otherwise.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Statistical analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We identify similar mature TLSs in patients with extra-nodal metastases (Extended Data Fig. 5b), which suggests that TLSs may develop in non-nodal sites and are associated with the response to ICB treatment.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > B cells localized in the context of TLSs
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Responder versus non-responder status was blinded until flow cytometry data capture and FlowJo analyses were completed.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Methods > Flow cytometric analyses of exosomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
B cells can secrete cytokines including TNF, IL-2, IL-6, and IFNγ, and through these cytokines activate and recruit other immune effector cells including T cells.
“B cells can also secrete an array of cytokines (including TNF, IL-2, IL-6 and IFNγ), through which they activate and recruit other immune effector cells, including T cells.”
The paper relies on this without support.
Switched memory B cells can differentiate into plasma cells.
“switched memory B cells (that can differentiate into plasma cells)”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Also, as a member of the 12-chemokine gene signature classifier33, its expression has been correlated with the presence of tumor-associated tertiary lymphoid structures50–52 which are rapidly emerging as a powerful prognostic marker in melanoma and a number of other cancer types53–55.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [54]
Experimental — accuracy not yet measuredIn the citing paper
“Tertiary lymphoid structures (TLS) have recently emerged as biomarkers of response to ICT across several tumor types, including lung cancer, melanoma, RCC, sarcoma, and urothelial cancer (163-167).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [164]
In the citing paper
“Presence of B cells in tumor was associated with a better response to neoadjuvant therapy with ICB in melanoma and renal cell carcinoma (Cabrita et al., 2020; Helmink et al., 2020).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Helmink et al., 2020
In the citing paper
“Tumor-infiltrating B cell populations in responder tumors were enriched in memory B cells; in contrast, naïve B cells were more prominent in non-responder tumors (Helmink et al., 2020).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Helmink et al., 2020
In the citing paper
“Mounting evidence on the role of the gut and tumor microbiome, stress, and diet in tumor immunity and response to ICB (Helmink et al., 2020) has created a foundation for emerging adjunct therapies.”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Helmink et al., 2020
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
“Figure: Extended Data Fig. 4 | Immune infiltrate is prognostic of improved diseasespecific survival in TCGA cutaneous melanoma cohort but not the clear-cell RCC cohort.”
§ B cells and tertiary lymphoid structures promote immunotherapy response > Extended Data
“b, Kaplan–Meier estimates of overall survival of MIC groups. c, Kaplan–Meier estimates of overall survival by B cell lineage scores shown by high and low groups dichotomized by median values.”
Citations
Cites
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InfluentialSTAR: ultrafast universal RNA-seq aligner
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“Significant progress has been made in this regard, with the identification of several validated biomarkers, particularly for immune checkpoint blockade (ICB) 1-10 .”
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Cited by
Sorted by citations
Items 801–900 of 1,004
Yin, Y., Ling, Y., Wei, X., He, C., Wang, B., Hu, C., Lin, W., Nie, R., Chen, J.-W., Lin, J., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.973085 · Cited by 27
“To further characterize the immune cell subsets of the TLSs in our cohort, CD20, CD4 CD8, CD21, and FOXP3 cells were detected in the non-mature or mature TLSs tumor samples using multiplex immunofluorescence methods (Figure 2) (28).”
MethodPredictability of B cell clonal persistence and immunosurveillance in breast cancer
Sammut, S., Galson, J. D., Minter, R., Sun, B., Chin, S., Mattos‐Arruda, L. D., Finch, D. K., Schätzle, S., Dias, J., Rueda, O. M., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01821-0 · Cited by 27
Regulatory Functions of Protein Tyrosine Phosphatase Receptor Type O in Immune Cells
Xie, F., Dong, H., & Zhang, H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.783370 · Cited by 26
Jiao, S., Xiong, Q., Yan, M., Zhan, X., Yang, Z., Peng, C. Y., Sun, B., Pang, D., & Liu, T. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003325 · Cited by 27
The Tumor-Specific Immune Landscape in HPV+ Head and Neck Cancer
Conarty, J. P., & Wieland, A. (2023) · Viruses · doi:10.3390/v15061296 · Cited by 27
Li, C., Clauson, R. M., Bugada, L. F., Ke, F., He, B., Yu, Z., Chen, H., Jacobovitz, B., Hu, H., Chuikov, P., et al. (2024) · ACS Nano · doi:10.1021/acsnano.3c13038 · Cited by 27
Wang, Y., Chen, W., Wang, Z., Dong, K., Zuo, L., Xu, D., Chen, J., Chen, W., Li, W., Liu, Z.-C., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-008613 · Cited by 28
“12 In the study of ccRCC, spatial transcrip-tomics analysis of TLSs in RCC recognized them as sites of in situ B cell maturation, and the presence of IgG-stained tumor cells correlated with enhanced therapeutic responses and longer progression-free survival (PFS) in patients.”
BackgroundSelf-citationStem-like CD8+ T cells in cancer
Steiner, C., Denlinger, N., Huang, X., & Yang, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1426418 · Cited by 28
Schuiveling, M., Liu, H., Eek, D., Breimer, G. E., Suijkerbuijk, K. P. M., Blokx, W. A. M., & Veta, M. (2025) · GigaScience · doi:10.1093/gigascience/giaf011 · Cited by 26
“For example, neutrophils are associated with an incr eased c hance of primary melanoma metastasizing, and B-cell presence is associated with response to immune checkpoint inhibition ther a py in melanoma [ 25 , 26 ].”
Tertiary Lymphoid Structures Across Organs: Context, Composition, and Clinical Levers
Guillaume, S. M., Beccaría, C. G., Iannacone, M., & Linterman, M. A. (2025) · Immunological Reviews · doi:10.1111/imr.70063 · Cited by 31
Su, L.-J., Wang, N.-N., Luo, R.-S., Ji, Z.-H., Gu, H., Yang, C., Xu, M.-X., Zhang, J., Chen, Q., Yu, M., et al. (2026) · Nature Biomedical Engineering · doi:10.1038/s41551-026-01640-8 · Cited by 33
Chemokine biology on immune checkpoint–targeted therapies
Letourneur, D., Danlos, F., & Marabelle, A. (2020) · European Journal of Cancer · doi:10.1016/j.ejca.2020.06.009 · Cited by 26
Kilvaer, T. K., Paulsen, E., Andersen, S., Rakaee, M., Bremnes, R. M., Busund, L., & Dønnem, T. (2020) · Carcinogenesis · doi:10.1093/carcin/bgaa105 · Cited by 26
Modulation of the Vascular-Immune Environment in Metastatic Cancer
He, B., & Ganß, R. (2021) · Cancers · doi:10.3390/cancers13040810 · Cited by 26
External cues to drive B cell function towards immunotherapy
Stoycheva, D., Şimşek, H., Weber, W., Hauser, A. E., & Klotzsch, E. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.02.026 · Cited by 25
Phanthunane, C., Wijers, R., de Herdt, M., Langeveld, T. P. M., Koljenović, S., Dasgupta, S., Sleijfer, S., de Jong, R. J. B., Hardillo, J. A., Balcioglu, H. E., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1882743 · Cited by 26
“response to ICI in the neoadjuvant setting of resectable melanoma and renal cell carcinoma.(41) We argue that the CD20 Cluster Score should be part of studies into new predictors for ICI treatment in OSCC.”
BackgroundTumor and Peripheral Immune Status in Soft Tissue Sarcoma: Implications for Immunotherapy
Sousa, L. M., Almeida, J. S., Fortes-Andrade, T., Santos-Rosa, M., Freitas-Tavares, P., Casanova, J., & Rodrigues‐Santos, P. (2021) · Cancers · doi:10.3390/cancers13153885 · Cited by 27
“found that B cell markers were the most differentially expressed genes in the tumors of STS responsive patients versus tumors of patients that did not respond to immunotherapy [49].”
BackgroundPrognostic Gene Expression Signature in Patients With Distinct Glioma Grades
Ssi, S. A., Chraa, D., Azhary, K. E., Sahraoui, S., Olive, D., & Badou, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.685213 · Cited by 26
B cell-related gene signature and cancer immunotherapy response
Lundberg, A., Li, B., & Li, R. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01674-6 · Cited by 27
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Tumor immunotherapy: Mechanisms and clinical applications
Nong, C., Guan, P., Li, L., Zhang, H., & Hu, H. (2022) · MedComm – Oncology · doi:10.1002/mog2.8 · Cited by 27
TIST: Transcriptome and Histopathological Image Integrative Analysis for Spatial Transcriptomics
Shan, Y., Zhang, Q., Guo, W., Wu, Y., Miao, Y., Xin, H., Lian, Q., & Gu, J. (2022) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2022.11.012 · Cited by 28
“TLS consists of ectopic aggregates of lymphoid cells in inflamed, infected, or tumoral tissues [25] and is reported to be closely related to tumor progression and metastasis, serving as a potential predictive marker for immunotherapy and prognosis [26].”
Artificial Intelligence-Assisted Transcriptomic Analysis to Advance Cancer Immunotherapy
Gui, Y., He, X., Yu, J., & Jing, J. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12041279 · Cited by 29
“Apart from T cells whose contents and types have effects on ICI therapy, other cell populations that correlate with the response to ICI have been determined recently [71].”
BackgroundZhang, B., Li, H., Li, H., Xiong, D., Zhang, L., & Sun, Z. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216105 · Cited by 27
Yang, G., Su, X., Huang, Y., Luo, G., Wang, Z., Cai, P., Zheng, Y., Bei, T., Huang, M., Bai, Y., et al. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04273-6 · Cited by 27
“Furthermore, TLSs were found to be more abundant in surgical tissues from pCR or MPR patients than those from nonpCR or non-MPR patients, which was consistent with previous reports linking TLSs to a favorable prognosis following immunotherapy [26, 27].”
BackgroundResultChen, W., Pan, X., Song, X., Liu, Z.-C., Xu, D., Chen, J., Dong, K., Di, S., Ye, J., Gan, S., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216963 · Cited by 26
Self-citationBessede, A., Peyraud, F., Moulec, S. L., Cousin, S., Cabart, M., Chomy, F., Rey, C., Lara, O., Odin, O., Nafia, I., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-1928 · Cited by 27
Immune Checkpoints in B Cells: Unlocking New Potentials in Cancer Treatment
Shi, X., Cheng, X., Jiang, A., Shi, W., Zhu, L., Mou, W., Glaviano, A., Liu, Z., Cheng, Q., Lin, A., et al. (2024) · Advanced Science · doi:10.1002/advs.202403423 · Cited by 25
Self-citationDendritic cells instruct T cell anti-tumor immunity and immunotherapy response
Xiao, Z., Wang, J., Yang, J., Guo, F., Zhang, L., & Zhang, L. (2025) · The Innovation Medicine · doi:10.59717/j.xinn-med.2025.100128 · Cited by 27
Yoshimitsu, M., Nakamura, M., Kano, S., Magara, T., Kato, H., Sakai, A., Sugiyama, M., Mizokami, M., & Morita, A. (2025) · Cancer Science · doi:10.1111/cas.70105 · Cited by 25
“In addition, TLS activate anti-tumor immunity and enhance the therapeutic effect of immune checkpoint inhibitors (ICI) [9].”
He, J. N., Gao, Y., Sun, Z., & Liu, S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1529403 · Cited by 26
Trontzas, I. P., & Syrigos, K. N. (2025) · Cancers · doi:10.3390/cancers17162639 · Cited by 27
“These peripheral B-cell profiles may reflect humoral immunity and mark TLS activity within tumors, which in turn correlates with improved immunotherapy outcomes [33,68].”
Xing, R. S., Mei, J., Zuo, Z., Zou, H., Yu, X.-J., Xu, J., Guo, R., Wei, W., & Zheng, L. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102298 · Cited by 27
“…(ICB), intra-tumor TLSs are induced, where memory B cells and plasma cells are found to activate naive T cells, enhancing anti-tumor responses 17 ; whereas, in patients with HCC receiving ICB therapy, noncanonical involuted TLSs are defined and beneficial for the expansion of cytotoxic and…”
Ho, W. J., Sharma, G., Zhu, Q., Stein-O’Brien, G., Durham, J. N., Anders, R. A., Popović, A., Mo, G., Kamel, I. R., Weiss, M. J., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000932 · Cited by 26
Immunotherapy in the Treatment of Urothelial Bladder Cancer: Insights From Single-Cell Analysis
Zang, J., Ye, K., Yang, F., Zhang, R., Chen, H., & Zhuang, G. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.696716 · Cited by 25
PLAN B for immunotherapy: Promoting and leveraging anti-tumor B cell immunity
Shi, Y. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.09.028 · Cited by 25
The prognostic value of TPM1–4 in hepatocellular carcinoma
Tian, Z., Zhao, J., & Wang, Y. (2021) · Cancer Medicine · doi:10.1002/cam4.4453 · Cited by 23
Ahmed, A., Köhler, S., Klotz, R., Giese, N., Hackert, T., Springfeld, C., Zörnig, I., Jäger, D., & Halama, N. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2027148 · Cited by 25
“in metastatic melanoma and renal cell carcinoma).(8) A compartmental investigation of the local and systemic immune landscape can expand our understanding of tumor immunity in PDA, especially with regard to B cell infiltration, including the formation of TLS.”
BackgroundNajem, H., Ott, M., Kassab, C., Rao, A. U. K., Rao, G., Marisetty, A., Sonabend, A. M., Horbinski, C., Verhaak, R. G. W., Shankar, A., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.157612 · Cited by 25
“In combination with our results, this suggests that the presence of dyads and clustering could serve as a biomarker, indicating immune checkpoint therapy responsiveness of individual tumors (24, 62), which is an area of future investigation, similar to the ongoing investigations in other cancers (63, 64).”
ResultCharacterization of the treatment-naive immune microenvironment in melanoma with BRAF mutation
Wang, M., Zadeh, S. H., Pizzolla, A., Thia, K. Y. T., Gyorki, D. E., McArthur, G. A., Scolyer, R. A., Long, G. V., Wilmott, J. S., Andrews, M. C., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004095 · Cited by 28
The Landscape of Immune Microenvironments in Racially Diverse Breast Cancer Patients
Hamilton, A. M., Hurson, A. N., Olsson, L. T., Walens, A., Nsonwu-Farley, J. S., Kirk, E. L., Abdou, Y. G., Downs‐Canner, S., Serody, J. S., Perou, C. M., et al. (2022) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-21-1312 · Cited by 25
Sato, Y. (2022) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2022.00104 · Cited by 25
“The enrichment/cluster of B-cells linked with localization of switched memory B-cell was assumed to correlate with better ICI efficacy, suggesting the feasibility of TLS analysis as ICI response prediction [38, 39].”
BackgroundMemory B‐cell diversity: From early generation to tissue residency and reactivation
Reusch, L., & Angeletti, D. (2023) · European Journal of Immunology · doi:10.1002/eji.202250085 · Cited by 27
Single-cell dissection of tumor microenvironmental response and resistance to cancer therapy
Luo, Y., & Liang, H. (2023) · Trends in Genetics · doi:10.1016/j.tig.2023.07.005 · Cited by 25
Posttransplant Tertiary Lymphoid Organs
Ruddle, N. H. (2023) · Transplantation · doi:10.1097/tp.0000000000004812 · Cited by 26
Brunner, M., Maier, K., Rümmele, P., Jacobsen, A., Merkel, S., Bénard, A., Krautz, C., Kersting, S., Grützmann, R., & Weber, G. F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051779 · Cited by 25
“CD20 positive B-cell infiltration has been associated with improved patient survival as well as increased immunotherapy response in various cancers [23,24].”
Backgroundvan Asten, S. D., de Groot, R., van Loenen, M. M., Castenmiller, S. M., de Jong, J., Monkhorst, K., Haanen, J. B. A. G., Amsen, D., Bex, A., Spaapen, R. M., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2020.1860482 · Cited by 22
Zhang, Y. X., Wang, F., Sun, H., Huang, Y., Gao, J., & Huang, H. (2021) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-021-03633-3 · Cited by 25
Self-citationBelderbos, R. A., Corneth, O. B. J., Dumoulin, D. W., Hendriks, R. W., Aerts, J. G. J. V., & Willemsen, M. (2023) · European Journal of Cancer · doi:10.1016/j.ejca.2023.113428 · Cited by 24
Soussan, S., Pupier, G., Cremer, I., Joubert, P.-E., Sautès‐Fridman, C., Fridman, W. H., & Sibéril, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1343020 · Cited by 26
Self-citationPhenotypic and spatial heterogeneity of CD8+ tumour infiltrating lymphocytes
Sun, Y., Yinwang, E., Wang, S., Wang, Z., Wang, F., Xue, Y., Zhang, W., Zhao, S., Mou, H., Chen, S., et al. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02104-w · Cited by 29
“TLSs are generally associated with improved survival outcomes and immunotherapy responses [265, 266, 269, 270], and yet, on scrutinisation, the localisation and maturity level of TLSs wield pivotal influences [267, 273], where extra-tumoural positioning and immaturity may underpin the negative…”
BackgroundHighly multiplexed imaging reveals prognostic immune and stromal spatial biomarkers in breast cancer
Eng, J. R., Bucher, E., Hu, Z., Walker, C. R., Risom, T., Angelo, M., Ericsson, P. I. G., Sanders, M. E., Chakravarthy, A. B., Pietenpol, J. A., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.176749 · Cited by 24
Ruffin, A. T., Casey, A. N., Kunning, S. R., MacFawn, I., Liu, Z., Arora, C., Rohatgi, A., Kemp, F., Lampenfeld, C., Somasundaram, A., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adh1315 · Cited by 24
Jiao, M., Guo, Y., Zhang, H., Wen, H., Chen, P., Wang, Z., Yu, B., Zhuma, K., Zhang, Y., Qie, J., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci181517 · Cited by 24
“B cells are considered to be the main TLS cell population (12, 26), and B cell–mediated formation of germinal centers is a marker of TLS maturation.”
Self-citationBroderick, C., Mezzadra, R., Sisso, E. M., Mbuga, F., Raghulan, R., Perez, A. C., Kulick, A. R., Jiang, L., Jiang, J., Ho, Y.-J., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1425 · Cited by 28
“TLSs are known positive prognostic indicators of response to immunotherapy (88, 89), and correspondingly, in our studies, one model in which TLSs emerged showed more durable responses than one without.”
Mucosal vaccination in mice provides protection from diverse respiratory threats
Zhang, H., Floyd, K. A., Fang, Z., Hoffmann, F. A., Lee, A. W. Q., Froggatt, H. M., Bharj, G., Xie, X., Eppler, H. B., Santagata, J. M., et al. (2026) · Science · doi:10.1126/science.aea1260 · Cited by 27
Wang, L., Wang, Y., Su, B. H., Yu, P., He, J., Meng, L., Xiao, Q., Sun, J., Zhou, K., Xue, Y., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-73700-1 · Cited by 24
Self-citationImmune Modulation in Lung Cancer: Current Concepts and Future Strategies
Gaissmaier, L., & Christopoulos, P. (2020) · Respiration · doi:10.1159/000510385 · Cited by 24
Kadono, Y., Kawaguchi, S., Nohara, T., Shigehara, K., Izumi, K., Kamijima, T., Seto, C., TAKANO, A., YOTSUYANAGI, S., Nakagawa, R., et al. (2021) · Anticancer Research · doi:10.21873/anticanres.14921 · Cited by 27
Immune Crosstalk Between Lymph Nodes and Breast Carcinomas, With a Focus on B Cells
Alberts, E., Wall, I., Calado, D. P., & Grigoriadis, A. E. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.673051 · Cited by 24
Cervera-Carrascón, V., Quixabeira, D. C. A., Santos, J. M., Havunen, R., Milenova, I. E., Verhoeff, J., Heiniö, C., Zafar, S., García-Vallejo, J. J., van Beusechem, V. W., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.706517 · Cited by 24
“Other upregulated genes in aPD-1 treated tumors might be remnants of initial effect of aPD-1, like the upregulation of genes related to complement system (37) or B-cells (38).”
BackgroundSingle-Cell Analysis Reveals Spatial Heterogeneity of Immune Cells in Lung Adenocarcinoma
Wang, Y., Li, X., Peng, S., Hu, H., Wang, Y., Shao, M., Feng, G. L., Liu, Y., & Bai, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.638374 · Cited by 23
Insights Into Unveiling a Potential Role of Tertiary Lymphoid Structures in Metastasis
Mustapha, R., Ng, K., Monypenny, J., & Ng, T. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.661516 · Cited by 23
“In conclusion, the role of TLS in cancer immunity and immunotherapy has been of major interest lately as multiple studies in cancer patients correlated the presence of mature, germinal center containing TLSs with response to immunotherapy (Cabrita et al., 2020; Helmink et al., 2020).”
BackgroundGenome edited B cells: a new frontier in immune cell therapies
Rogers, G. L., & Cannon, P. M. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.09.019 · Cited by 27
Intratumoral therapies and in-situ vaccination for melanoma
Huppert, L. A., & DAUD, A. I. (2022) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2021.1890512 · Cited by 24
“TLSs are often, but not always, correlated with a positive prognosis.(12) Similar to lymph nodes, TLSs can contain a substantial diversity of lymphocytes, including naive and activated conventional T cells, regulatory T (Treg) cells, B cells and dendritic cells (DCs).”
BackgroundDai, L., Mugaanyi, J., Cai, X., Dong, M., Lu, C., & Lu, C. (2022) · Scientific Reports · doi:10.1038/s41598-022-17954-x · Cited by 23
Song, J., Ruze, R., Chen, Y., Xu, R., Yin, X., Wang, C., Xu, Q., & Zhao, Y. (2022) · BMC Cancer · doi:10.1186/s12885-022-09983-6 · Cited by 23
“Besides, it has been reported that tumor-infiltrating B cells contribute to a better response to ICB therapy, and tumors of responders showed a higher infiltrating level of memory B cells, while lower infiltrating level of naïve B cells than tumors of nonresponders [50].”
BackgroundLiu, J., Chen, H. H., Qiao, G., Zhang, J., Zhang, S., Zhu, C., Chen, Y., Tang, J., Li, W., Wang, S., et al. (2022) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-022-03288-0 · Cited by 24
Self-citationBallot, E., Ladoire, S., Routy, B., Truntzer, C., & Ghiringhelli, F. (2020) · Cancers · doi:10.3390/cancers12092418 · Cited by 24
Li, G.-Q., Wang, Y.-K., Zhou, H., Jin, L.-G., Wang, C.-Y., Albahde, M., Wu, Y., Li, H.-Y., Zhang, W.-K., Li, B.-H., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.630355 · Cited by 24
“…indicates that increased immune infiltration of M2like macrophages, CD8 T, NK, mast cells, B cells, and type 2 T helper cells in the EW microenvironment are significantly associated with poor prognosis in EW patients (Kastrinakis et al., 2000; Guzik and Barañska, 2013; Hernandez et al., 2018).”
BackgroundVito, A., Salem, O., El-Sayes, N., MacFawn, I., Portillo, A. L., Milne, K., Harrington, D., Ashkar, A. A., Wan, Y., Workenhe, S. T., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02375-9 · Cited by 24
Chang, T., Spathis, A., Schäffer, A. A., Gavrielatou, N., Kuo, F., Jia, D., Mukherjee, S., Sievers, C. M., Economopoulou, P., Anastasiou, M., et al. (2024) · Annals of Oncology · doi:10.1016/j.annonc.2024.11.008 · Cited by 26
Huang, Y., Du, Z., Lai, Z., Wen, D., Huang, L., He, M., Wu, Z., Li, H., OuYang, H., Wu, W., et al. (2024) · Advanced Science · doi:10.1002/advs.202405749 · Cited by 25
Abdulrahman, Z., Slieker, R. C., McGuire, D., Welters, M. J. P., van Poelgeest, M. I. E., & van der Burg, S. H. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-011308 · Cited by 24
Zhang, L., Kandadi, H., Yang, H., Cham, J., He, T., Oh, D. Y., Sheikh, N. A., & Fong, L. H. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0252 · Cited by 23
“In addition, the B-cell repertoire canmediate response tocheckpoint inhibitors (31, 32).”
BackgroundAnti-CD19 CAR T cells potently redirected to kill solid tumor cells
Ambrose, C. M., Su, L., Wu, L., Dufort, F. J., Sanford, T., Birt, A., Hackel, B. J., Hombach, A. A., Abken, H., Lobb, R. R., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0247701 · Cited by 23
“Finally, the importance of immunologically relevant T cell activation has been demonstrated in the immune checkpoint field, with defined roles for organized secondary and tertiary lymphoid organs becoming apparent [43-46].”
BackgroundLymph Node Immune Profiles as Predictive Biomarkers for Immune Checkpoint Inhibitor Response
Goode, E., Torres, E. T. R., & Irshad, S. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.674558 · Cited by 23
Lineage Reprogramming of Effector Regulatory T Cells in Cancer
Dixon, M. L., Leavenworth, J. D., & Leavenworth, J. W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.717421 · Cited by 23
Yang, H., Ma, W., Sun, B., Fan, L., Xu, K., Hall, S. R. R., Al-Hurani, M. F., Schmid, R. A., Peng, R., Hida, T., et al. (2021) · Translational Lung Cancer Research · doi:10.21037/tlcr-21-734 · Cited by 22
“Among those, TLSs, ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumours represent highly interesting components that could robustly predict the response to ICIs (44-46).”
BackgroundSuzuki, S., Haratani, K., Hayashi, H., Chiba, Y., Tanizaki, J., Kato, R., Mitani, S., Kawanaka, Y., Kurosaki, T., Hasegawa, Y., et al. (2021) · European Journal of Cancer · doi:10.1016/j.ejca.2021.11.011 · Cited by 23
A Pan-Cancer Analysis of Tumor-Infiltrating B Cell Repertoires
Yu, K., Ravoor, A., Malats, N., Pineda, S., & Sirota, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.790119 · Cited by 23
“Indeed, several studies have shown that an enrichment of B cells in tertiary lymphoid structures was predictive of response to immune checkpoint inhibitors in melanoma, soft-tissue sarcoma, and renal cell carcinoma (60, 61).”
BackgroundTrigos, A., Pasam, A., Banks, P. D., Wallace, R., Guo, C. W., Keam, S. P., Thorne, H., kConFab, Mitchell, C., Lade, S., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003744 · Cited by 24
“In 20–26 Further studies of the interface between tumor genomics and the TIME are warranted to understand how best to personalize therapies.”
Tertiary lymphoid structures in lung adenocarcinoma: characteristics and related factors
Ren, F., Xie, M., Gao, J., Wu, C., Xu, Y. Y., Zang, X., Ma, X., Deng, H., Song, J., Huang, A., et al. (2022) · Cancer Medicine · doi:10.1002/cam4.4796 · Cited by 23
Self-citationFuente, F. D. L., Belkhir, R., Henry, J., Nguyen, C. D., Pham, T., Germain, V., Gavand, P., Labadie, C., Brière, C., Lauret, A., et al. (2022) · RMD Open · doi:10.1136/rmdopen-2022-002612 · Cited by 23
Tertiary Lymphoid Structures: A Potential Biomarker for Anti-Cancer Therapy
Zou, J. P., Zhang, Y., Zeng, Y., Peng, Y., Liu, J., Xiao, C., & Wu, F. (2022) · Cancers · doi:10.3390/cancers14235968 · Cited by 24
B cells in tumor metastasis: friend or foe?
Xu, Y., Mao, Y., Lv, Y., Tang, W., & Xu, J. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.79482 · Cited by 23
“As mentioned above, an increase in B cells can contribute to an effective T-cell response after immune checkpoint blockade [56].”
BackgroundInfluentialBiomarker-Driven Personalization of Neoadjuvant Immunotherapy in Melanoma
Hoeijmakers, L. L., Reijers, I. L. M., & Blank, C. U. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0352 · Cited by 24
Self-citationLv, K., Sun, M., Fang, H., Wang, J., Lin, C., Liu, H., Zhang, H., Li, H., He, H., Gu, Y., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007669 · Cited by 24
Wu, W., Li, H., Wang, Z., Dai, Z., Liang, X., Luo, P., Liu, K., Zhang, H., Zhang, N., Li, S., et al. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e23915 · Cited by 24
“The ubiquitous presence of TLS has been unveiled in cancers at all stages, in primary as well as metastasis [14].”
BackgroundChen, C., Ma, J., Pi, C., Huang, W., Zhang, T., Fu, C., Liu, W., & Yang, Y. (2023) · Cell Discovery · doi:10.1038/s41421-023-00568-6 · Cited by 22
Self-citationFeng, C., Tao, Y., Yu, C., Wang, L., Liu, X., & Cao, Y. (2023) · Cancer Gene Therapy · doi:10.1038/s41417-023-00663-6 · Cited by 23
“The presence of B cells was associated with improved prognosis in melanoma and sarcoma patients, but not in renal cell carcinoma patients [43 – 45], suggesting that the density of B cells in different tumor types in fl uences prognosis.”
Self-citationWang, Z., Zhao, Y., Wo, Y., Peng, Y., Hu, W., Wu, Z., Liu, P., Shang, Y., Liu, C., Chen, X., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216951 · Cited by 23
Shi, X., Jiang, A., Qiu, Z., Lin, A., Liu, Z., Zhu, L., Mou, W., Cheng, Q., Zhang, J., Miao, K., et al. (2024) · Frontiers of Medicine · doi:10.1007/s11684-024-1094-2 · Cited by 24
Nie, J., Zhang, S., Guo, Y., Liu, C., Shi, J., Wu, H., Na, R., Liang, Y., Yu, S., Quan, F., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-24-1173 · Cited by 22
Self-citationArciga, B. M., Walters, D. M., Kimchi, E. T., Staveley-O’Carroll, K. F., Li, G., Teixeiro, E., Rachagani, S., & Kaifi, J. T. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217361 · Cited by 24
Li, C., Wang, P., Dong, Z., Cao, W., Su, Y., Zhang, J., Zhao, S., Wang, Z., Lei, Z., Shi, L., et al. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03341-7 · Cited by 22
“Recent studies have demonstrated a correlation between the presence of tertiary lymphoid structures (TLS) in tumors and an improved prognosis in patients with solid cancers [24–26].”
Self-citationNeoadjuvant Therapy for Mucosal Head and Neck Squamous Cell Carcinoma
Contrera, K. J., Kansara, S., Goyal, N., Mady, L. J., Puram, S. V., Young, G. D., Zandberg, D. P., Uppaluri, R., Ferrarotto, R., Holsinger, F. C., et al. (2025) · JAMA Otolaryngology–Head & Neck Surgery · doi:10.1001/jamaoto.2025.0410 · Cited by 22
Song, D., Wang, Y., Zhu, K., Tian, L., Gao, Q., Zhou, J., Fan, J., & Wang, X. (2020) · World Journal of Surgical Oncology · doi:10.1186/s12957-020-01953-1 · Cited by 22
“Recent studies demonstrated that the integration of TIICs and clinicopathologic characteristics can be a prognostic predictive model and predict the response of immune therapy [13, 26].”
BackgroundBrase, J. C., Walter, R. F. H., Savchenko, A., Gusenleitner, D., Garrett, J., Schimming, T. T., Váraljai, R., Castelletti, D., Kim, J., Dakappagari, N. K., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3586 · Cited by 22
“Helmink and colleagues (14) demonstrated that this T-cell/B-cell profile was independent of BRAF mutation status, consistent with our results.”
ResultB Cells Are Required to Generate Optimal Anti-Melanoma Immunity in Response to Checkpoint Blockade
Singh, S., Roszik, J., Saini, N., Singh, V. K., Bavisi, K., Wang, Z., Vien, L., Yang, Z., Kundu, S., Davis, R. E., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.794684 · Cited by 22
“Recently, some clinical studies also showed a key role of B cells in response to immune checkpoint blockade therapy (18, 19).”
BackgroundResult
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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