Inflammatory B cells correlate with failure to checkpoint blockade in melanoma patients

Jonge, Kaat de; Tillé, Laure; Lourenço, João; Hajjami, Hélène Maby–El; Nassiri, Sina; Racle, Julien; Gfeller, David; Delorenzi, Mauro; Verdeil, Grégory; Baumgaertner, Petra; Speiser, Daniel E.

doi:10.1080/2162402x.2021.1873585

Cited by 25 publications

(21 citation statements)

References 50 publications

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“…Chronic inflammation is a hallmark of TNBC. 11 TIB cells have been associated with chronic inflammatory signatures [15][16][17][18]37 and have been shown to secrete several inflammatory cytokines in breast cancer 38 . While previous studies have shown that tumor cells are capable of activating inflammatory signaling cascades in B cells 35,38 , the effects of this interaction on tumor cells are less clear.…”

Section: B Cells Induce Chronic Inflammation In Tnbcmentioning

confidence: 99%

Tumor-B-Cell Interactions Promote Isotype Switching to an Immunosuppressive IgG4 Antibody Response Through Upregulation of IL-10 in Triple Negative Breast Cancers

Toney

Opdenaker

Cicek

et al. 2021

Preprint

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Background: Triple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine the role of IgG4 in TNBC. Methods: We performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20 + TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests. Results: Our findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape. Conclusions: These findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals that suppress antibody driven immune responses

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Section: B Cells Induce Chronic Inflammation In Tnbcmentioning

confidence: 99%

Tumor-B-Cell Interactions Promote Isotype Switching to an Immunosuppressive IgG4 Antibody Response Through Upregulation of IL-10 in Triple Negative Breast Cancers

Toney

Opdenaker

Cicek

et al. 2021

Preprint

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“…We have previously shown that melanoma cells can potently induce both differentiation and cytokine secretion in B cells derived from the tumor tissue and peripheral blood of melanoma patients [ 3 ]. These results have been further supported at the single-cell level in various B cell subpopulations from human melanoma metastases [ 8 ] and in the most recent ex vivo stimulation assays of B cells from melanoma patients [ 18 ]. Interestingly, the spectrum of melanoma B cell-derived expression signatures includes cytokines with documented immunostimulatory as well as immunosuppressive activities [ 3 , 18 ].…”

Section: Introductionmentioning

confidence: 72%

“…These results have been further supported at the single-cell level in various B cell subpopulations from human melanoma metastases [ 8 ] and in the most recent ex vivo stimulation assays of B cells from melanoma patients [ 18 ]. Interestingly, the spectrum of melanoma B cell-derived expression signatures includes cytokines with documented immunostimulatory as well as immunosuppressive activities [ 3 , 18 ]. This observation may help to explain the sometimes contradictory reports of the direct pro- and anti-tumorigenic functions of human B cells and the association of B cell numbers with disease outcome in melanoma patients.…”

Section: Introductionmentioning

confidence: 72%

Loss of Lymphotoxin Alpha-Expressing Memory B Cells Correlates with Metastasis of Human Primary Melanoma

et al. 2021

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Activated antigen-experienced B cells play an unexpected complex role in anti-tumor immunity in human melanoma patients. However, correlative studies between B cell infiltration and tumor progression are limited by the lack of distinction between functional B cell subtypes. In this study, we examined a series of 59 primary and metastatic human cutaneous melanoma specimens with B cell infiltration. Using seven-color multiplex immunohistochemistry and automated tissue imaging and analysis, we analyzed the spatiotemporal dynamics of three major antigen-experienced B cell subpopulations expressing lymphotoxin alpha (LTA/TNFSF1) or interleukin-10 (IL-10) outside tertiary lymphoid structures. The expression of both LTA and IL-10 was not restricted to a particular B cell subtype. In primary melanomas, these cells were predominantly found at the invasive tumor-stroma front and, in metastatic melanomas, they were also found in the intratumoral stroma. In primary melanomas, decreased densities of LTA+ memory-like and, to a lesser extent, activated B cells were associated with metastasis. Compared with metastatic primary tumors, B cell infiltrates in melanoma metastases were enriched in both LTA+ memory-like and LTA+ activated B cells, but not in any of the IL-10+ B cell subpopulations. Melanoma disease progression shows distinct dynamics of functional B cell subpopulations, with the regulation of LTA+ B cell numbers being more significant than IL-10+ B cell subpopulations.

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“…Chronic inflammation is a hallmark of TNBC [ 11 ]. TIB cells have been associated with chronic inflammatory signatures [ 15 – 18 , 37 ] and have been shown to secrete several inflammatory cytokines in breast cancer [ 38 ]. While previous studies have shown that tumor cells are capable of activating inflammatory signaling cascades in B cells [ 35 , 38 ], the effects of this interaction on tumor cells are less clear.…”

Section: Resultsmentioning

confidence: 99%

Tumor-B-cell interactions promote isotype switching to an immunosuppressive IgG4 antibody response through upregulation of IL-10 in triple negative breast cancers

et al. 2022

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Background Triple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine if IgG4 + B cells are present and determine the mechanisms driving isotype switching in TNBC. Methods We performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20+ TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests. Results Our findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape. Conclusions These findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals such as IL-10 and IL-4 that drive class switching to an IgG4 + subtype which may suppress antibody driven immune responses. The presence of IgG4 + B cells may serve as a biomarker for poor prognosis.

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Inflammatory B cells correlate with failure to checkpoint blockade in melanoma patients

Cited by 25 publications

References 50 publications

Tumor-B-Cell Interactions Promote Isotype Switching to an Immunosuppressive IgG4 Antibody Response Through Upregulation of IL-10 in Triple Negative Breast Cancers

Tumor-B-Cell Interactions Promote Isotype Switching to an Immunosuppressive IgG4 Antibody Response Through Upregulation of IL-10 in Triple Negative Breast Cancers

Loss of Lymphotoxin Alpha-Expressing Memory B Cells Correlates with Metastasis of Human Primary Melanoma

Tumor-B-cell interactions promote isotype switching to an immunosuppressive IgG4 antibody response through upregulation of IL-10 in triple negative breast cancers

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