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A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases.

ABSTRACT: In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T-cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the antitumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the antitumor immune response in HGSOC metastases.Unmatched pre and post-chemotherapy HGSOC metastases were studied. B-cell localization was assessed by immunostaining. Their cytokines and chemokines were measured by a multiplex assay, and their phenotype was assessed by flow cytometry. Further in vitro and in vivo assays highlighted the role of B cells and plasma cell IgGs in the development of cytotoxic responses and dendritic cell activation.B cells mainly infiltrated lymphoid structures in the stroma of HGSOC metastases. There was a strong B-cell memory response directed at a restricted repertoire of antigens and production of tumor-specific IgGs by plasma cells. These responses were enhanced by chemotherapy. Interestingly, transcript levels of CD20 correlated with markers of immune cytolytic responses and immune complexes with tumor-derived IgGs stimulated the expression of the costimulatory molecule CD86 on antigen-presenting cells. A positive role for B cells in the antitumor response was also supported by B-cell depletion in a syngeneic mouse model of peritoneal metastasis.Our data showed that B cells infiltrating HGSOC omental metastases support the development of an antitumor response. Clin Cancer Res; 23(1); 250-62. ©2016 AACR.

SUBMITTER: Montfort A

PROVIDER: S-EPMC5928522 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases.

Montfort Anne A Pearce Oliver O Maniati Eleni E Vincent Benjamin G BG Bixby Lisa L Böhm Steffen S Dowe Thomas T Wilkes Edmund H EH Chakravarty Probir P Thompson Richard R Topping Joanne J Cutillas Pedro R PR Lockley Michelle M Serody Jonathan S JS Capasso Melania M Balkwill Frances R FR

Clinical cancer research : an official journal of the American Association for Cancer Research 20160627 1

<h4>Purpose</h4>In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8<sup>+</sup> T-cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the antitumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the antitumor immune response in HGSOC metastases.<h4>Experimental design</h4>Unmatched pre and post-chemotherapy HGSOC metastases w ...[more]

PMID: 27354470

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Project description:BackgroundThe prognosis of high grade serous ovarian cancer (HGSOC) patients is closely related to the immune microenvironment and immune response. Based on this, the purpose of this study was to construct a model to predict chemosensitivity and prognosis, and provide novel biomarkers for immunotherapy and prognosis evaluation of HGSOC.MethodsGSE40595 (38 samples), GSE18520 (63 samples), GSE26712 (195 samples), TCGA (321 samples) and GTEx (88 samples) were integrated to screen differential expressed genes (DEGs) of HGSOC. The prognosis related DEGs (DEPGs) were screened through overall survival analysis. The DEGs-encoded protein-protein interaction network was constructed and hub genes of DEPGs (DEPHGs) were generated by STRING. Immune characteristics of the samples were judged by ssGSEA, ESTIMATE and CYBERSORT. TIMER was used to analyze the relationship between DEPHGs and tumor-infiltrating immunocytes, as well as the immune checkpoint genes, finally immune-related DEPHGs (IDEPHGs) were determined, and whose expression in 12 pairs of HGSOC tissues and tumor-adjacent tissues were analyzed by histological verification. Furthermore, the chemosensitivity genes in IDEPHGs were screened according to GSE15622 (n = 65). Finally, two prediction models of paclitaxel sensitivity score (PTX score) and carboplatin sensitivity score (CBP score) were constructed by lasso algorithm. The area under curve was calculated to estimate the accuracy of candidate gene models in evaluating chemotherapy sensitivity.Results491 DEGs were screened and 37 DEGs were identified as DEPGs, and 11 DEPHGs were further identified. Among them, CXCL13, IDO1, PI3, SPP1 and TRIM22 were screened as IDEPHGs and verified in the human tissues. Further analysis showed that IDO1, PI3 and TRIM22 could independently affect the chemotherapy sensitivity of HGSOC patients. The PTX score was significantly better than TRIM22, PI3, SPP1, IDO1 and CXCL13 in predicting paclitaxel sensitivity, so was CBP score in predicting carboplatin sensitivity. What's more, both of the HGSOC patients with high PTX score or high CBP score had longer survival time.ConclusionsFive IDEPHGs identified through comprehensive bioinformatics analysis were closely related with the prognosis, immune microenvironment and chemotherapy sensitivity of HGSOC. Two prediction models based on IDEPHGs might have potential application of chemotherapy sensitivity and prognosis for patients with HGSOC.

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A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases.

Publications

A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases.

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