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Myeloid-derived suppressive cells promote B cell-mediated immunosuppression via transfer of PD-L1 in glioblastoma

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Abstract

The potent immunosuppression induced by glioblastoma (GBM) is one of the primary obstacles to finding effective immunotherapies. One hallmark of the GBM-associated immunosuppressive landscape is the massive infiltration of myeloid-derived suppressor cells (MDSC) and, to a lesser extent, regulatory T cells (Treg) within the tumor microenvironment. Here, we showed that regulatory B cells (Breg) are a prominent feature of theGBMmicroenvironment in both preclinical models and clinical samples. Forty percent of GBM patients (n = 60) scored positive for B-cell tumor infiltration. Human and mouse GBM-associated Bregs were characterized by immunosuppressive activity toward activated CD8+ T cells, the overexpression of inhibitory molecules PD-L1 and CD155, and production of immunosuppressive cytokines TGFb and IL10. Local delivery of B cell-depleting anti-CD20 immunotherapy improved overall survival of animals (IgG vs. anti- CD20 mean survival: 18.5 vs. 33 days, P= 0.0001), suggesting a potential role of Bregs in GBM progression. We unveiled that GBM-associated MDSCs promoted regulatory B-cell function by delivering microvesicles transporting membrane-bound PD-L1, able to be up-taken by tumoral B cells. The transfer of functional PD-L1 via microvesicles conferred Bregs the potential to suppress CD8+ T-cell activation and acquisition of an effector phenotype. This work uncovered the role of B cells in GBM physiopathology and provides a mechanism by which the GBM microenvironment controls B cell-mediated immunosuppression.

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Lee-Chang, C., Rashidi, A., Miska, J., Zhang, P., Pituch, K. C., Hou, D., … Lesniak, M. S. (2019). Myeloid-derived suppressive cells promote B cell-mediated immunosuppression via transfer of PD-L1 in glioblastoma. Cancer Immunology Research, 7(12), 1928–1943. https://doi.org/10.1158/2326-6066.CIR-19-0240

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