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
Cites
Cytoscape: A software Environment for integrated models of biomolecular interaction networks
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InfluentialSTAR: ultrafast universal RNA-seq aligner
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Influentiallimma powers differential expression analyses for RNA-sequencing and microarray studies
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PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
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“Significant progress has been made in this regard, with the identification of several validated biomarkers, particularly for immune checkpoint blockade (ICB) 1-10 .”
Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients
Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., Karpinets, T. V., Prieto, P. A., Vicente, D., Hoffman, K., Wei, S. C., et al. (2018) · Science · doi:10.1126/science.aan4236 · Cited by 4,812
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IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade
Ayers, M., Lunceford, J., Nebozhyn, M., Murphy, E., Loboda, A., Kaufman, D. R., Albright, A., Cheng, J. D., Kang, S. P., Shankaran, V., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci91190 · Cited by 3,788
Cited by
Sorted by citations
Items 701–800 of 1,004
Tertiary lymphoid tissues: a regional hub for kidney inflammation
Sato, Y., Tamura, M., & Yanagita, M. (2021) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfab212 · Cited by 32
Liang, W., He, X., Bi, J., Hu, T., & Sun, Y. (2021) · Oncology Reports · doi:10.3892/or.2021.8159 · Cited by 34
B cell–derived IL-27 promotes control of persistent LCMV infection
Pratumchai, I., Žák, J., Huang, Z., Min, B., Oldstone, M. B. A., & Teijaro, J. R. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2116741119 · Cited by 32
Tertiary Lymphoid Structures as Mediators of Immunotherapy Response
Vaghjiani, R. G., & Skitzki, J. J. (2022) · Cancers · doi:10.3390/cancers14153748 · Cited by 33
“Multiomic data indicate that TLS, and certain cellular subtypes within these lymphoid aggregates, may play an important role in the tumor responses of melanoma and renal cell carcinoma to immune checkpoint blockade [43].”
BackgroundHigh endothelial venules as potential gateways for therapeutics
Hussain, B., Kasinath, V., Ashton-Rickardt, G. P., Clancy, T. E., Uchimura, K., Tsokos, G. C., & Abdi, R. (2022) · Trends in Immunology · doi:10.1016/j.it.2022.07.002 · Cited by 35
Li, P., Liang, Y., Zeng, B., Yang, G., Zhu, C., Zhao, K., Xu, Z., Wang, G., Han, C., Ye, H., et al. (2022) · European Journal of Radiology · doi:10.1016/j.ejrad.2022.110309 · Cited by 32
Understanding the Tumor Immune Microenvironment in Renal Cell Carcinoma
Shapiro, D. D., Dolan, B. K., Laklouk, I. A., Rassi, S., Ložar, T., Emamekhoo, H., Wentland, A. L., Lubner, M. G., & Abel, E. J. (2023) · Cancers · doi:10.3390/cancers15092500 · Cited by 35
“These intratumoral B cells were shown to localize within TLSs, and patients with higher TLS density were more likely to respond to ICI therapy [64].”
BackgroundPeripheral helper T cells, mavericks of peripheral immune responses
Yoshitomi, H. (2023) · International Immunology · doi:10.1093/intimm/dxad041 · Cited by 32
“Indeed, in RA, the disappearance of TLSs with molecularly targeted drugs is associated with a good prognosis (29); TLSs within malignancies are associated with a good patient prognosis in many types of cancer (30–32).”
BackgroundXing, A., Lv, D., Wu, C., Zhou, K., Zhao, T., Zhao, L., Wang, H., & Feng, H. (2024) · Current Genomics · doi:10.2174/0113892029278082240118053857 · Cited by 33
Tumor-infiltrating B cells: Their dual mechanistic roles in the tumor microenvironment
Xue, D., Hu, S., Zheng, R., Luo, H., & Ren, X. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117436 · Cited by 36
Tang, C., Zhang, M., Jia, H., Wang, T., Wu, H., Xu, K., Ren, T., & Liang, L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1516737 · Cited by 35
“Consequently, changes in SIRI could re fl ect not only systemic immune status but also the formation of local immune structures like TLS (38).”
Lin, J., Jiang, S., Chen, B., Du, Y., Qin, C., Song, Y., Peng, Y., Ding, M., Wu, J., Lin, Y., et al. (2024) · Advanced Science · doi:10.1002/advs.202410998 · Cited by 34
PPP2R1A mutations portend improved survival after cancer immunotherapy
Dai, Y., Knisely, A. T., Yano, M., Dang, M., Hinchcliff, E., Lee, S., Welp, A. M., Chelvanambi, M., Lastrapes, M. J., Liu, H., et al. (2025) · Nature · doi:10.1038/s41586-025-09203-8 · Cited by 32
Self-citationSpatial architecture of development and disease
Lázár, E., & Lundeberg, J. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-025-00892-5 · Cited by 38
B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity
Chen, C., An, M., Zheng, H., Pang, M., Li, Y., Diao, X., Luo, Y., Lin, Y., Liu, D., Li, W., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2025.12.011 · Cited by 33
Current and future biomarkers for outcomes with immunotherapy in non-small cell lung cancer
Duchemann, B., Remón, J., Naigeon, M., Cassard, L., Jouniaux, J.-M., Boselli, L., Grivel, J., Auclin, É., Desnoyer, A., Besse, B., et al. (2021) · Translational Lung Cancer Research · doi:10.21037/tlcr-20-839 · Cited by 33
“Apparition of TLS during treatment in various tumor types appears to be associated with favorable evolution during ICI treatment (80-82), although this is yet to be evaluated in lung cancer.”
BackgroundApplications of Single-Cell Omics to Dissect Tumor Microenvironment
Guo, T., Li, W., & Cai, X. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.548719 · Cited by 33
“Our growing understanding of the TME has laid scientific foundation for cancer immunotherapy, which is arguably one of the greatest breakthroughs in cancer therapeutics over the past decade (Hodi et al., 2010; Robert et al., 2014; Garon et al., 2015; Ribas and Wolchok, 2018).”
BackgroundDing, J., He, X., Cheng, X., Cao, G., Chen, B., Chen, S., & Xiong, M. (2021) · World Journal of Surgical Oncology · doi:10.1186/s12957-021-02204-7 · Cited by 32
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Yamada, Y., Nguyen, T. T., Impellizzieri, D., Mineura, K., Shibuya, R., Gomariz, Á., Haberecker, M., Nilsson, J., Nombela‐Arrieta, C., Jungraithmayr, W., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36924-z · Cited by 32
Dissecting Tumor-Immune Microenvironment in Breast Cancer at a Spatial and Multiplex Resolution
Tzoras, E., Zerdes, I., Tsiknakis, N., Manikis, G. C., Mezheyeuski, A., Bergh, J. C. S., Matikas, A., & Foukakis, T. (2022) · Cancers · doi:10.3390/cancers14081999 · Cited by 30
Opportunities and challenges to engineer 3D models of tumor-adaptive immune interactions
Visalakshan, R. M., Lowrey, M. K., Sousa, M. G. C., Helms, H. R., Samiea, A., Schutt, C. E., Moreau, J. M., & Bertassoni, L. E. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1162905 · Cited by 32
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Comparative analysis of immune infiltrates in head and neck cancers across anatomical sites
Muijlwijk, T., Nijenhuis, D., Ganzevles, S., Brink, A., Ke, C.-L., Fass, J. N., Rajamanickam, V., Leemans, C., Koguchi, Y., Fox, B. A., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007573 · Cited by 34
Seizing the fate of lymph nodes in immunotherapy: To preserve or not?
Xu, Z., Li, Z., Cao, L., Zhong, N., Liu, X.-H., Wang, G.-R., Xiao, Y., Liu, B., & Bu, L. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216740 · Cited by 31
Sustained innate interferon is an essential inducer of tertiary lymphoid structures
Calvanese, A. L., Cecconi, V., Stäheli, S., Schnepf, D., Nater, M., Pereira, P., Gschwend, J., Heikenwälder, M. F., Schneider, C., Ludewig, B., et al. (2024) · European Journal of Immunology · doi:10.1002/eji.202451207 · Cited by 32
“We have developed a robust model for TLS induction in the lungs that recapitulates the TLS seen in different human pathologies [6, 13, 51, 52].”
B cells and tertiary lymphoid structures in cancer therapy response
Hegoburu, A., Amer, M., Frizelle, F., & Purcell, R. V. (2025) · BJC Reports · doi:10.1038/s44276-025-00146-1 · Cited by 31
“While the role of T cells in this response is de fi ned, that of B cells and TLSs in antitumour immunity and in therapy remains unclear [46, 47].”
Sawada, J., Kikuchi, Y., Duah, M., Herrera, J. L., Kanamori, F., Csomós, K., Stansel, T., Hiraoka, N., Yoshida, M., Walter, J. E., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02259-8 · Cited by 36
“…in dense clusters as TLS unlike T cells, which were found in high density around indicated that the presence of abundant B cells associated with TLS is the most important prognostic factor in predicting patient survival, suggesting a vital role of intratumoral B cells in antitumor immunity 8–10 .”
InfluentialToripalimab for the treatment of melanoma
Tang, B., Chi, Z., & Guo, J. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2020.1762561 · Cited by 30
Regulation of neuroinflammation by B cells and plasma cells
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Humoral immune responses: Unsung heroes of the war on cancer
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Sun, S., Xu, L., Zhang, X., Pang, L., Long, Z., Deng, C., Zhu, J., Zhou, S., Wan, L., Pang, B., et al. (2021) · Cancers · doi:10.3390/cancers13071639 · Cited by 32
“These results were consistent with recent studies that B cells were associated with immunotherapy response to ICB in patients with metastatic melanoma, RCC and soft-tissue sarcoma [54,55].”
ResultZhao, Z., Ding, H., Lin, Z.-B., Qiu, S., Yi-ran, Z., Guo, Y., Chu, X., Sam, L. I., Pan, J., & Pan, Y.-L. (2021) · International Journal of Medical Sciences · doi:10.7150/ijms.56347 · Cited by 29
“TLS is a crucial component of tumor immune microenvironment [5, 48], which not only facilitating the recruitment of immune cells or play an anti-tumor role, but also act as a predictor for the prognosis of various cancer [4, 7, 10, 15, 22, 24, 34, 39].”
BackgroundRing, S. S., Cupovic, J., Onder, L., Lütge, M., Perez‐Shibayama, C., Gil‐Cruz, C., Scandella, E., Martin, A. D., Mörbe, U., Hartmann, F., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25057-w · Cited by 31
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He, Y., Han, Y., Fan, A., Li, D., Wang, B., Ji, K., Wang, X., Zhao, X., & Lu, Y. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03667-2 · Cited by 34
“We also include CD20-labeled B lymphocytes (15), CD66b-labeled neutrophils (16), CD11c-labeled dendritic cells (DCs) (17) and CD56-labeled natural killer (NK) cells (18), which all play an important roles in the occurrence and development of tumors.”
BackgroundRossi, A., Belmonte, B., Carnevale, S., Liotti, A., Rosa, V. D., Jaillon, S., Piconese, S., & Tripodo, C. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.933113 · Cited by 30
Miller, R. A., Luke, J. J., Hu, S., Mahabhashyam, S., Jones, W. B., Marron, T. U., Merchan, J. R., Hughes, B. G. M., & Willingham, S. B. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005802 · Cited by 32
Yin, G., Liu, L., Yu, T., Yu, L., Feng, M., Zhou, C., Wang, X., Teng, G., Ma, Z., Zhou, W., et al. (2024) · Genome Medicine · doi:10.1186/s13073-024-01286-8 · Cited by 30
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Chimeric Antigen Receptor T Cell Therapy for Hepatocellular Carcinoma: Where Do We Stand?
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Reste, M., Ajazi, K., Sayi‐Yazgan, A., Janković, R., Bufan, B., Brandau, S., Bækkevold, E. S., Petitprez, F., Lindstedt, M., Adema, G. J., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1439413 · Cited by 32
“The presence of TLS has been shown to be associated with an improved response to immunotherapy in soft-tissue sarcoma (11, 18), melanoma (19, 20), clear-cell renal cell carcinoma (12, 20), breast cancer (21) and lung cancer (22, 23).”
Self-citationGobbini, É., Hubert, M., Doffin, A., Eberhardt, A., Hermet, L., Li, D., Duplouye, P., Ghamry-Barrin, S., Berthet, J., Benboubker, V., et al. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-24-0421 · Cited by 33
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“In addition, B cells present in the TME or clustering in tertiary lymphoid structures might have a role in mediating response to ICI in mesothelioma and other cancers 158–164 .”
Millar, E. K. A., Browne, L. H., Šlapetová, I., Shang, F., Ren, Y., Bradshaw, R., Brauer, H. A., O’Toole, S. A., Beretov, J., Whan, R. M., et al. (2020) · Cancers · doi:10.3390/cancers12092365 · Cited by 30
“More recently, B-cells and tertiary lymphoid structures (TLS) were shown to correlate with more potent responses to immune checkpoint blockade (ICB) in melanoma [34].”
BackgroundClonal tracing reveals diverse patterns of response to immune checkpoint blockade
Gu, S. S., Wang, X., Hu, X. S., Jiang, P., Li, Z., Traugh, N. C., Bu, X., Tang, Q., Wang, C., Zeng, Z., et al. (2020) · Genome biology · doi:10.1186/s13059-020-02166-1 · Cited by 29
A High-Dimensional Window into the Micro-Environment of Triple Negative Breast Cancer
Nederlof, I., Horlings, H. M., Curtis, C. N., & Kok, M. (2021) · Cancers · doi:10.3390/cancers13020316 · Cited by 33
Conversations that count: Cellular interactions that drive T cell fate
Duckworth, B. C., & Groom, J. R. (2021) · Immunological Reviews · doi:10.1111/imr.12945 · Cited by 32
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Cancer-Homing CAR-T Cells and Endogenous Immune Population Dynamics
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Barth, D. A., Stanzer, S., Terzic, J. A., Bauernhofer, T., Absenger, G., Szkandera, J., Gerger, A., Smolle, M. A., Hutterer, G. C., Ahyai, S., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.840207 · Cited by 30
Tertel, T., Schoppet, M., Stambouli, O., Al-Jipouri, A., James, P. F., & Giebel, B. (2022) · Cytotherapy · doi:10.1016/j.jcyt.2022.02.003 · Cited by 31
The Host-Microbiome Response to Hyperbaric Oxygen Therapy in Ulcerative Colitis Patients
Gonzalez, C. G., Mills, R. H., Kordahi, M. C., Carrillo-Terrazas, M., Secaira-Morocho, H., Widjaja, C. E., Tsai, M. S., Mittal, Y., Yee, B. A., Vargas, F., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.03.008 · Cited by 31
Neutrophils: Musketeers against immunotherapy
Zahid, K. R., Raza, U., Tumbath, S., Jiang, L., Xu, W., & Huang, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.975981 · Cited by 31
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Self-citationA Single-Cell Tumor Immune Atlas for Precision OncologyPreprint
Nieto, P., Elosua-Bayés, M., Trincado, J. L., Marchese, D., Massoni-Badosa, R., Salvany, M., Henriques, A. R., Mereu, E., Moutinho, C., Ruiz, S., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.10.26.354829 · Cited by 31
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Synergistic induction of tertiary lymphoid structures by chemoimmunotherapy in bladder cancer
Zhang, L., Zhang, R., Jin, D., Zhang, T., Shahatiaili, A., Zang, J., Wang, L., Pu, Y., Zhuang, G., Chen, H., et al. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02598-7 · Cited by 30
Self-citationNeoadjuvant systemic therapy for hepatocellular carcinoma
Chick, R. C., Ruff, S. M., & Pawlik, T. M. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1355812 · Cited by 28
Next-generation CD40 agonists for cancer immunotherapy
Andersson, H., Nyesiga, B., Hermodsson, T., Smith, K. E., Hägerbrand, K., Lindstedt, M., & Ellmark, P. (2024) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2024.2357714 · Cited by 30
Tertiary lymphoid structures: new immunotherapy biomarker
Yang, F., Yang, J., Wu, M., Chen, C. Y., & Chu, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1394505 · Cited by 33
“The density of CD20 + B cells and TLSs were higher in responders than in non-responders in neoadjuvant melanoma cohort, particularly in early on-treatment samples (107).”
BackgroundKan, L., Yu, Y., Wang, Y., Shi, L., Fan, T., Chen, H., & Ren, C. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02328-4 · Cited by 32
Heij, L. R., Tan, X., Kather, J. N., Niehues, J. M., Sivakumar, S., Heussen, N. M., van der Kroft, G., Damink, S. W. M. O., Lang, S. A., Aberle, M. R., et al. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10030490 · Cited by 29
Targeting Erbin in B cells for therapy of lung metastasis of colorectal cancer
Shen, T., Liu, J., Wang, C., Rixiati, Y., Shi, L., Cai, L.-D., Zhao, Y., & Li, J. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00501-x · Cited by 30
Feng, B., & Heß, J. (2021) · Cancers · doi:10.3390/cancers13051162 · Cited by 29
“The presence of TLS has been linked with improved survival across many cancer types, including HNSCC [133], and several studies provide compelling clinical evidence for the potential role of B cells and TLS in the response to ICI treatment, with implications for the development of new biomarkers and therapeutic target…”
BackgroundKim, H. A. J., Zeng, P. Y., Shaikh, M. H., Mundi, N., Ghasemi, F., Gravio, E. J. D., Khan, H., MacNeil, S. D., Khan, M. I., Patel, K., et al. (2021) · Oral Oncology · doi:10.1016/j.oraloncology.2021.105260 · Cited by 29
Lü, Y., Ng, A. H. C., Chow, F. E., Everson, R. G., Helmink, B. A., Tetzlaff, M. T., Thakur, R., Wargo, J. A., Cloughesy, T. F., Prins, R. M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24293-4 · Cited by 30
Self-citationActivated B Cells and Plasma Cells Are Resistant to Radiation Therapy
Pietryga, I. F., Miyauchi, S., Kim, S. S., Sanders, P. D., Sumner, W., Zhang, L., Mundt, A. J., Califano, J. A., & Sharabi, A. B. (2021) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2021.08.037 · Cited by 29
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Self-citationNext-generation sequencing: unraveling genetic mechanisms that shape cancer immunotherapy efficacy
Halima, A., Vuong, W., & Chan, T. A.-T. (2022) · Journal of Clinical Investigation · doi:10.1172/jci154945 · Cited by 31
Perrino, M., Vincenzo, F. D., Cordua, N., Borea, F., Aliprandi, M., Santoro, A., & Zucali, P. A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1121557 · Cited by 30
“Moreover, immunotherapy seems to promote TLS formation and activity and this can explain the possible role of TLS and B cells infiltration as positive predictive biomarker of response to ICIs in different cancer types (69, 71, 76, 77).”
BackgroundDeterminants of anti-PD1 response and resistance in clear cell renal cell carcinomaPreprint
Au, L., Hatipoglu, E., de Massy, M. R., Litchfield, K., Rowan, A., Thompson, R. H., Schnidrig, D., Byrne, F., Beattie, G., Horswell, S. D., et al. (2021) · medRxiv · doi:10.1101/2021.03.19.21253661 · Cited by 29
Cancer immunology and immunotherapy
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Zhang, D., Ni, Y., Wang, Y., Feng, J., Zhuang, N., Li, J., Liu, L., Shen, W., Zheng, J., Zheng, W., et al. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04336-8 · Cited by 28
Martins, C. P., Rasbach, E., Heppt, M. V., Singh, P. K., Kulcsár, Z., Holzgruber, J., Chakraborty, A., Mucciarone, K., Kleffel, S., Brandenburg, A., et al. (2024) · Science Advances · doi:10.1126/sciadv.adi2012 · Cited by 29
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“48 Our study highlighted the prognostic value of a high density of TLSs for patients with TNBC. Importantly, our re-sults demonstrated a substantial association between TLS density Particularly, in highly aggressive tumors, TB is associated with tumor growth and metastasis, predicting a poor…”
BackgroundHumoral determinants of checkpoint immunotherapy
Dai, Y., Aizenbud, L., Qin, K., Austin, M. R., Jaycox, J. R., Cunningham, J., Wang, E. Y., Zhang, L., Fischer, S., Carroll, S. M., et al. (2025) · Nature · doi:10.1038/s41586-025-09188-4 · Cited by 29
Entangled cellular and molecular relationships at the sensory neuron-cancer interface
Sur, D., Zeng, Y., Kobayashi, H. H., Zhi, X., Goetz, M. R., Müller, C., Zavitsanou, A., Picoli, C. C., Matos, A. A. M., Pareja, J. R., et al. (2025) · Neuron · doi:10.1016/j.neuron.2025.07.017 · Cited by 31
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“Some recent studies showed that TLS enhance the response to immunotherapy in patients with melanoma or lung cancer and therefore might serve as a biomarker of anti PD-1 therapy [18, 31].”
BackgroundShi, C., Wang, Y., Xue, J., & Zhou, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.940288 · Cited by 31
The Immune Contexture of Liposarcoma and Its Clinical Implications
Resag, A., Toffanin, G., Benešová, I., Müller, L., Potkrajcic, V., Ozaniak, A., Lischke, R., Bartůňková, J., Rosato, A., Jöhrens, K., et al. (2022) · Cancers · doi:10.3390/cancers14194578 · Cited by 30
“Especially tumor-infiltrating lymphocytes (TILs) play a key role in predicting response to immunotherapy [12,13], which was also reported for STS including LPS [14,15].”
BackgroundLiang, H., Zhang, Z., Guan, Z., Zheng, S., Lou, J., Liu, W., Cai, Q., & Si, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1096220 · Cited by 30
“Numerous studies have demonstrated the intensive infiltration of plasma cells (3, 34) and CD8+ cells (35), indicating a favorable prognosis.”
BackgroundMethodInfluentialSelf-citationWang, M., Zhai, R., Wang, M., Zhu, W., Zhang, J., Yu, M., Zhang, W., Ye, J., & Liu, L. (2023) · Molecular Oncology · doi:10.1002/1878-0261.13403 · Cited by 28
‘Persistent germinal center responses: slow-growing trees bear the best fruits’
Matz, H. C., McIntire, K. M., & Ellebedy, A. H. (2023) · Current Opinion in Immunology · doi:10.1016/j.coi.2023.102332 · Cited by 27
Ding, L., Sun, L., Bu, M. T., Zhang, Y., Scott, L. N., Prins, R. M., Su, M. A., Lechner, M. G., & Hugo, W. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1176994 · Cited by 31
“The presence of TLS has been correlated with improved survival after ICI therapy in melanoma (28, 29) and other cancers (30, 31).”
BackgroundYin, X., Wang, H., Li, R., Song, X., Zhang, T., Liang, Y., Chen, Y., Yu, X., Mao, Q., Xia, W., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-006939 · Cited by 27
“6 The development of TLSs has been provided to depend on an analogous chemokine and cytokine network.”
Xu, F., Zhu, H., Dong, Y., Li, L., Liu, N., & Yuan, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1244256 · Cited by 28
Unravelling immune microenvironment features underlying tumor progression in the single-cell era
Du, Q., An, Q., Zhang, J., Liu, C., & Hu, Q. (2024) · Cancer Cell International · doi:10.1186/s12935-024-03335-z · Cited by 27
“Mean-while, switched memory B-cells are precursors of anti-inflammatory specific memory cells and plasma besides promoting antigen presentation [74, 75].”
BackgroundD’Orsi, L., Capasso, B., Lamacchia, G., Pizzichini, P., Ferranti, S., Liverani, A., Fontana, C., Panunzi, S., Gaetano, A. D., & Presti, E. L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111588 · Cited by 29
Mannose Enhances Immunotherapy Efficacy in Ovarian Cancer by Modulating Gut Microbial Metabolites
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Radandish, M., Mashhadi, N., Aghayan, A. H., Taghizadeh, M., Salehianfard, S., Yahyazadeh, S., Vakili, O., & Igder, S. (2025) · Experimental Hematology and Oncology · doi:10.1186/s40164-025-00695-8 · Cited by 27
“Various innate and adaptive immune cells such as dendritic cells, macrophages, different subsets of T and B lymphocytes, as well as fibroblastic reticular cells (FRCs), follicular dendritic cells (FDCs), and PNAd + high endothelial venules (HEVs) can be detected in TLSs [222, 223].”
Yang, J., Wang, C., Fu, D., Ho, L., Galani, K., Chen, L., Gonzalez, J., Fu, J. Y. L., Huang, A. Y., Frederick, D. T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62878-5 · Cited by 28
Lin, Y., Ou, D., Su, Y., Hsu, C., Hsiao, C., Ko, B., Chen, S., Wang, J., Wang, J.-H., Wu, Y., et al. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.08.035 · Cited by 32
Labadie, B. W., Balar, A. V., & Luke, J. J. (2021) · Cancers · doi:10.3390/cancers13215415 · Cited by 30
Accounting for B-cell Behavior and Sampling Bias Predicts Anti–PD-L1 Response in Bladder Cancer
Dyugay, I. A., Lukyanov, D. K., Turchaninova, M. A., Serebrovskaya, E. O., Bryushkova, E. A., Zaretsky, A. R., Khalmurzaev, O., Matveev, V. B., Shugay, M., Shelyakin, P. V., et al. (2022) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-21-0489 · Cited by 29
“Multiple studies have demonstrated substantial involvement of CD4þ T cells (66, 67), NK cells (68), and B cells (1–5) in cancer immunosurveillance and immunotherapy responses (1, 2).”
BackgroundNakamura, M., Magara, T., Kano, S., Matsubara, A., Kato, H., & Morita, A. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.811586 · Cited by 27
“MCPyV-negative, i.e., ultraviolet-induced, MCCs have a higher tumor mutation burden and more neoantigens than MCPyVpositive MCC. Ultraviolet-induced MCCs, however, are not more responsive to ICIs than virus-induced MCCs (5).”
BackgroundInfluentialZhao, H., Wang, H., Zhao, Y., Sun, Q., & Ren, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.877689 · Cited by 28
Self-citationThe Multi-Dimensional Biomarker Landscape in Cancer Immunotherapy
Lee, J. Y., Kannan, B., Lim, B. Y., Li, Z., Lim, A. H., Loh, J. W., Ko, T. K., Ng, C. C. Y., & Chan, J. Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23147839 · Cited by 29
Self-citation
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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