Mutation load and an effector T-cell gene signature may distinguish immunologically distinct and clinically relevant lymphoma subsets

Bolen, Christopher R.; McCord, Ronald; Huet, Sarah; Frampton, Garrett M.; Bourgon, Richard; Jardin, Fabrice; Dartigues, Peggy; Punnoose, Elizabeth A.; Szafer-Glusman, Edith; Xerri, Luc; Sujobert, Pierre; Salles, Gilles; Venstrom, Jeffrey M.

doi:10.1182/bloodadvances.2016000786

Cited by 44 publications

(29 citation statements)

References 41 publications

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“…3C) and macrophages (Spearman correlation 0.71, p < 0.01) as estimated by xCell 34 . Established signatures describing the inflammatory TME and possible response to anti-PD-1 therapy (tumor inflammatory score 35 , interferon gamma 36 , T cell exhaustion 37 , and T cell effector 38 signatures) additionally showed a high linear correlation with our TIPB signature (Spearman correlation ≥ 0.85, BH adjusted p < 0.01, Supplementary Fig. 3D).…”

Section: Resultsmentioning

confidence: 76%

“…7A). Published signatures describing melanoma-associated inflammation and possible response to anti-PD-1 therapy (tumor inflammatory score 35 , interferon gamma 36 , T cell exhaustion 37 , and T cell effector 38 signatures) highly correlated with our TIPB signature (Spearman correlation 0.7–0.9, BH adjusted p < 0.01, Supplementary Fig. 7B) and showed a significant decrease on anti-CD20 therapy (one-sided, paired t -test, BH adjusted p = 0.01, df = 5, t = 3.11–5.46, Fig.…”

Section: Resultsmentioning

confidence: 99%

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B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

et al. 2019

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Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Current theories on regulation of inflammation center on anti-tumor T cell responses. Here we show that tumor associated B cells are vital to melanoma associated inflammation. Human B cells express pro- and anti-inflammatory factors and differentiate into plasmablast-like cells when exposed to autologous melanoma secretomes in vitro. This plasmablast-like phenotype can be reconciled in human melanomas where plasmablast-like cells also express T cell-recruiting chemokines CCL3, CCL4, CCL5. Depletion of B cells in melanoma patients by anti-CD20 immunotherapy decreases tumor associated inflammation and CD8+ T cell numbers. Plasmablast-like cells also increase PD-1+ T cell activation through anti-PD-1 blockade in vitro and their frequency in pretherapy melanomas predicts response and survival to immune checkpoint blockade. Tumor associated B cells therefore orchestrate and sustain melanoma inflammation and may represent a predictor for survival and response to immune checkpoint blockade therapy.

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Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

et al. 2019

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“…Figure 5C) and macrophages (Spearman correlation 0.71, p < 0.01) as estimated by xCell 34 . Established signatures describing the inflammatory TME and possible response to anti-PD1 therapy (tumor inflammatory score 35 , interferon gamma 36 , T-cell exhaustion 37 , and T-cell effector 38…”

Section: Melanoma Conditioned Medium Induces a Plasmablast-like Dominmentioning

confidence: 99%

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

Griss

Bauer

Wagner

et al. 2018

Preprint

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Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Established mechanisms that underlie therapy response and resistance center on anti-tumor T cell responses.Here we show that tumor-associated B cells are vital to tumor associated inflammation.Autologous B cells were directly induced by melanoma conditioned medium, expressed proand anti-inflammatory factors, and differentiated towards a plasmablast-like phenotype in vitro .We could identify this phenotype as a distinct cluster of B cells in an independent public single-cell RNA-seq dataset from melanoma tumors. There, plasmablast-like tumor-associated B cells showed expression of CD8+T cell-recruiting chemokines such as CCL3, CCL4, CCL5 and CCL28. Depletion of tumor associated B cells in metastatic melanoma patients by anti-CD20 immunotherapy decreased overall inflammation and CD8+T cell numbers in the human melanoma TME. Conversely, the frequency of plasmablast-like B cells in pretherapy melanoma samples predicted response and survival to immune checkpoint blockade in two independent cohorts. Tumor-associated B cells therefore orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and may represent a predictor for response and survival to immune checkpoint blockade in human melanoma.2 Cancers such as melanoma, lung, and kidney cancer often present with an inflamed but immunosuppressive tumor microenvironment (TME). Immune checkpoint blocking (ICB) antibodies have significantly improved cancer therapy by overcoming inhibition of T cell effector functions. Yet, a considerable number of patients does not benefit from ICB therapy 1 . It is therefore key to understand the mechanisms that regulate inflammation within the TME to develop novel therapies and improve patient survival. B cells promote both acute immune-associated inflammation for protection against foreign pathogens as well as chronic inflammation in autoimmune diseases and persistent infection. Mouse cancer models show that tumor-associated B cells (TAB) promote tumor inflammation 2,3 but may also inhibit anti-tumor T cell-dependent therapy responses 4-7 . The immuno-inhibitory function of TAB in these models resembles that of regulatory B cells (Breg), which are an established source of inhibitory cytokines such as IL-10 and TGF-b (reviewed in 8 ). In human cancer, Breg were described by either phenotyping, direct detection of immunoinhibitory cytokines or surface molecules, and/or immunosuppressive function 4,[9][10][11][12][13] .Often Breg frequencies increase with tumor progression and are enriched in tumors compared to peripheral blood or adjacent normal tissue. Increased IL-10 + B cell numbers can also be accompanied by increased numbers of CD4 + CD25 +/high CD127 low/and Foxp3 + Tregs in tumor tissues 10,12,14,15 which were independently associated with tumor progression or reduced patient survival.In human melanoma, up to 33% of the immune cells can be TAB 16,17 and phenotypic analysis has revealed CD20+ TAB (reviewed in 18 ) and CD1...

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“…Based on our findings and recent reports that GPR18 was involved in regulating CD8 + T-cell environment, we further examined if GPR18-high tumors would have any functional indications on T-cell activity by assessing three well-established T-cell immunoreactive functionality scores. These were the cytolytic score (CYT), Teff, and the antitumor IFNG signature score [54][55][56] . As shown in Fig.…”

Section: Unfavorable-prognostic Cancers Display Elevated Il6/pd-l2mentioning

confidence: 99%

Omics-wide quantitative B-cell infiltration analyses identify GPR18 for human cancer prognosis with superiority over CD20

Liu

Wang

et al. 2020

Commun Biol

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Tumor-infiltrating B lymphocyte (TIL-B), and TIL-B-related biomarkers have clinical prognostic values for human cancers. CD20 (encoded by MS4A1) is a widely used TIL-B biomarker. Using TCGA-quantitative multiomics datasets, we first cross-compare prognostic powers of intratumoral CD20 protein, mRNA and TIL-B levels in pan-cancers. Here, we show that MS4A1 and TIL-B are consistently prognostic in 5 cancers (head and neck, lung, cervical, kidney and low-grade glioma), while unexpectedly, CD20 protein levels lack quantitative correlations with MS4A1/TIL-B levels and demonstrate limited prognosticity. Subsequent bioinformatics discovery for TIL-B prognostic gene identifies a single gene, GPR18 with standalone prognosticity across 9 cancers (superior over CD20), with further validations in multiple non-TCGA cohorts. GPR18's immune signature denotes major B-cell-T-cell interactions, with its intratumoral expression strongly tied to a "T-cell active", likely cytolytic, status across human cancers, suggesting its functional link to cytolytic T-cell activity in cancer. GPR18 merits biological and clinical utility assessments over CD20.

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Mutation load and an effector T-cell gene signature may distinguish immunologically distinct and clinically relevant lymphoma subsets

Abstract: Key Points• Low mutation load is associated with a benefit from rituximab maintenance.• The T eff signature correlates with high mutation load, is prognostic, and may distinguish immunologically distinct FL subgroups.

Cited by 44 publications

References 41 publications

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

Omics-wide quantitative B-cell infiltration analyses identify GPR18 for human cancer prognosis with superiority over CD20

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