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Cited by 2,731Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

B cells and tertiary lymphoid structures promote immunotherapy response

Open access
Helmink, Beth A., Reddy, Sangeetha M., Gao, Jianjun, Zhang, Shaojun, Basar, Rafet, Thakur, Rohit, Yizhak, Keren, Sade-Feldman, Moshe +52 more·2020·Nature
DOI 10.1038/s41586-019-1922-8PMC PMC8762581
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Abstract

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.

Integrity signals

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Crossref · 10.1038/s41586-019-1922-8

Cites

66 of 66 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 11 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    The findings were corroborated in translational studies of separate melanoma and sarcoma cohorts treated with ICB.

    “Moreover, these findings were corroborated in translational studies of separate cohorts of patients with melanoma36 and sarcoma37 who were treated with ICB.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Findingcitation

    B cells were not significantly associated with pathological response rates in a trial of neoadjuvant targeted therapy in BRAF-mutated melanoma.

    “B cells were not significantly associated with pathological response rates in an analogous trial of neoadjuvant-targeted therapy in patients with BRAF-mutated melanoma38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Findingcitation

    High B cell lineage scores in responders were replicated in an additional melanoma cohort (OpACIN-neo) treated with neoadjuvant versus adjuvant checkpoint blockade (n = 12 responders, 6 non-responders).

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018). source

      Not checked in the free run.

  • Findingown data

    B cell signatures alone predicted response in univariable analyses (odds ratio 2.6, P = 0.02 for the trial; odds ratio 2.9, P = 0.03 for combined melanoma cohorts).

    “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)”
    Quote in the paperSubstantial claim
  • Findingown data

    B cell signatures did not predict response in multivariable analyses when other components of the immune cell infiltrate were considered.

    “but not in multivariable analyses when considering other components of the immune cell infiltrate”
    Quote in the paperSubstantial claim
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 28

  • May combine two claims.

    Findingown data

    In the neoadjuvant melanoma cohort, B-cell-related genes MZB1, JCHAIN, and IGLL5 were expressed at significantly higher levels in responders than non-responders at baseline (P < 0.001), with over-representation relative to T cells and other immune markers, among seven evaluable responders and nine non-responders.

    “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)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The melanoma immune classes had no clear association with known genomic subtypes of melanoma (BRAF, NRAS, NF1, or triple wild type) or with disease site (nodal or non-nodal).

    “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)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Bulk RNA-seq pathway analysis showed increased immune signalling pathways in responders versus non-responders, including T cell receptor signalling, MHC-mediated antigen presentation and processing, TH1/TH2 differentiation, and costimulatory signalling associated with T cell signalling.

    “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”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The CyTOF tumour analysis included 9 responders and 9 non-responders, while the peripheral blood mononuclear cell analysis included 8 responders and 8 non-responders.

    “For tumour, this included 9 responders and 9 non-responders, and for peripheral blood mononuclear cells, 8 responders and 8 non-responders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In TCGA-KIRC clear-cell RCC, similar immune classes were observed, but immune infiltration was not associated with survival (P = 0.24).

    “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)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The final stage III TCGA-SKCM cohort consisted of 136 patients.

    “yielding a final stage III TCGA-SKCM cohort of n = 136.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Single-cell sequencing produced a median of about 1.4 million paired-end reads and a median of 2,588 detected genes per cell.

    “resulting in a median of approximately 1.4 million paired-end reads and a median of 2,588 genes detected per cell.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the neoadjuvant melanoma cohort, CD20+ B cell density, TLS density, and TLS-to-tumour area ratio were higher in responders than non-responders in early on-treatment samples (P = 0.0008, 0.001, and 0.002), but not all markers reached significance at baseline (P = 0.132, 0.078, and 0.037).

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BCR analysis showed significantly increased clonal counts for IgH and IgL (P = 0.001 and 0.004) and increased BCR diversity in responders versus non-responders (P = 0.002 and 0.0008).

    “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)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Plasma cells were increased in responders compared with non-responders, but this did not reach significance (P = 0.3) and was largely driven by one patient.

    “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)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    After excluding cases without expression data, 526 TCGA-KIRC cases were included in subsequent analysis.

    “For TCGA-KIRC, the cases without available expression data were excluded and a total of 526 cases were taken into subsequent analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No significant associations were found between individual B cell clusters G1-G4 and clinical outcome, probably due to limited sample size.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the RCC pre-surgical ICB cohort, increased infiltration of CD20+ cells and TLS density were associated with response to treatment, and these TLSs were morphologically similar to those in melanoma.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TLSs are associated with response in RCC, as they are in melanoma.

    “TLSs are associated with response in RCC similar to those observed in melanoma.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    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 each).

    “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)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the RCC cohort, B cell signatures predicted response in univariable analysis (odds ratio 61.2, P = 0.05) but not in multivariable analysis.

    “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”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Nine of the 136 TCGA-SKCM samples lacked survival data, leaving 127 samples for overall survival analysis.

    “Survival data were missing for 9 of 136 samples, so n = 127 samples were available for overall survival analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In single-cell RNA-seq from an independent metastatic melanoma cohort, B cells were significantly enriched in tumours from responders versus non-responders and were predictive of response (odds ratio 1.05, P = 0.02).

    “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)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The selected unsupervised clustering solution used k=11 and had a median robustness score of 0.96.

    “This process yielded a median robustness measure of 0.96 for the selected k=11.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Twenty-eight pre-treatment RCC samples were available across three arms: nivolumab (6), nivolumab plus bevacizumab (14), and nivolumab plus ipilimumab (8).

    “There are 28 available pre-treatment samples from 3 arms: nivolumab (n = 6), nivolumab plus bevacizumab (n = 14) and nivolumab plus ipilimumab (n = 8).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CD20+ B cells were localized in TLSs of tumours from responders and colocalized with CD4+, CD8+, and FOXP3+ T cells.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    B cells probably act together with other immune subsets and are not acting in isolation.

    “which suggests that B cells probably act together with other immune subsets and are not acting in isolation”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    B cells have previously been shown to be positively associated with responses to chemotherapy in other cancer types.

    “however, B cells have previously been shown to be positively associated with responses to chemotherapy in other cancer types39,40.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The RCC multivariable analysis was limited by sample size.

    “however, sample size was again limited”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study did not use statistical methods to predetermine sample size.

    “No statistical methods were used to predetermine sample size.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    After reviewing a Spearman correlation matrix, a sequencing event from one library pool that correlated poorly with other pools from the same RNA sample was excluded before BAM files were merged at the sample level.

    “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.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Samples containing fewer than 200 CD45+CD19+ B cells were excluded from downstream analyses.

    “Samples with fewer than 200 CD45+CD19+ B cells were not used for downstream analyses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Switched memory B cells observed in responders could potentially contribute to anti-tumour response by producing antibodies against tumours.

    “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.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Switched memory B cells can differentiate into plasma cells.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Transmission electron micrographs showed Dynabeads with exosomes present after immunocapture.

    “Representative transmission electron micrographs showing Dynabead with exosomes present after immunocapture.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    For each patient, the same number of CD45+ cells (384 per plate) was collected and sequenced, making the cell count per patient equal.

    “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”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    RNA integrity was evaluated with an Agilent 2100 Bioanalyzer and RNA 6000 Nano Chip, using smear analysis to measure DV200 and initial RNA concentration.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Technical replicates were limited to one per time point because of limited patient-derived tissue and prioritization for other studies.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Nanoimager images showed beads coated with CD63+ exosomes compared with isotype control.

    “Nanoimager-captured images of the beads coated with CD63+ exosomes as compared with isotype control.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Protein targets with a signal-to-noise ratio below 2 were excluded from downstream analysis.

    “Protein targets with a signal to noise ratio less than 2 were removed from downstream analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For multiplex immunofluorescence, five random areas per sample were evaluated blindly by a pathologist at 20× magnification.

    “Five random areas on each sample were analysed blindly by a pathologist at 20× magnification.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Only in-frame productive BCR clonotypes were retained for subsequent analysis.

    “Only in-frame productive clonotypes were taken into subsequent analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Running tumour and peripheral blood samples from melanoma patients treated with ICB together in mass cytometry eliminated batch effect.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The experiments were not randomized.

    “The experiments were not randomized”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    One exosome sample had an erroneous Nanosight measurement and was excluded from that measurement, but all samples were included in flow cytometric analyses.

    “For one sample, the Nanosight measurement was erroneous and excluded. All samples were included in the flow cytometric analyses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Sequencing reads containing at least 15 consecutive low-quality bases (phred score below 20) were filtered out of the FASTQ files.

    “The reads that had ≥ 15 contiguous low-quality bases (phred score < 20) were removed from the FASTQ files.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Investigators were not blinded to allocation during experiments or outcome assessment unless otherwise stated.

    “investigators were not blinded to allocation during experiments and outcome assessment unless stated otherwise.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Similar mature TLSs were identified in patients with extra-nodal metastases, suggesting that TLSs may develop in non-nodal sites and are associated with response to ICB treatment.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Responder versus non-responder status remained blinded until flow cytometry data capture and FlowJo analyses were finished.

    “Responder versus non-responder status was blinded until flow cytometry data capture and FlowJo analyses were completed.”
    Quote in the paperNot a substantial claim
43 of 43

  • 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)”
2 of 2

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?

  • Tumor-associated tertiary lymphoid structures are emerging as a powerful prognostic marker in melanoma and a number of other cancer types.

    “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]

    The section “B cells prognostic in TCGA analysis” describes existing evidence for a potential prognostic role for TLSs in melanoma and other cancer types. It also reports improved survival for a melanoma group with higher B-cell expression, but that is not a direct measure of TLSs. The source therefore supports the emerging prognostic association, not the stronger description of TLSs as a powerful prognostic marker across those cancers. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Tertiary lymphoid structures have emerged as biomarkers of response to immune checkpoint therapy across several tumor types including lung cancer, melanoma, RCC, sarcoma, and urothelial cancer.

    “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]

  • Presence of B cells in tumor is associated with better response to neoadjuvant ICB in melanoma and renal cell carcinoma.

    “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

  • Tumor-infiltrating B cell populations in responder tumors are enriched in memory B cells, while naïve B cells are more prominent in non-responder tumors.

    “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

  • Evidence supports a role for the gut and tumor microbiome, stress, and diet in tumor immunity and in response to immune checkpoint blockade.

    “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.

  • Survival endpoint differs between the figure title and description

    Minor

    The figure title identifies disease-specific survival as the endpoint, but the figure description and Methods identify overall survival. These are different endpoints.

1 of 1

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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
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-01-15
Volume
577
Issue
7791
Pages
549-555
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1922-8
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
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
  • AIM at Melanoma
  • Parker Institute for Cancer Immunotherapy
  • National Institutes of Health (W81XWH, CA- 016672)
  • University of Texas MD Anderson Cancer Center ((CA016672), T32 CA 009599, P30-CA-016672)
  • National Cancer Institute (T32CA009666, R01CA213233, CA213233, R01CA195733, CA195733, P30CA008748, T32CA009599, P30CA016672, P01CA117969)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
B cells, tertiary lymphoid structures, immune checkpoint blockade, cancer immunotherapy response, melanoma, renal cell carcinoma, switched memory B cells, B cell clonal expansion, tumor immune microenvironment, predictive biomarkers, MCP-counter, tumor-infiltrating immune cells
MeSH terms
Tertiary Lymphoid Structures, RNA-Seq, B-Lymphocytes, Carcinoma, Renal Cell, Clone Cells, Humans, Immunologic Memory, Immunotherapy, Melanoma, Neoplasm Metastasis, Phenotype, Prognosis, Receptors, Immunologic, Mass Spectrometry, T-Lymphocytes, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Dendritic Cells, Follicular, Single-Cell Analysis, Cell Cycle Checkpoints, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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