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

Catalina Lee-Chang, Aida Rashidi, Jason Miska, Peng Zhang, Katarzyna C. Pituch, David Hou, Ting Xiao, Mariafausta Fischietti, Seong Jae Kang, Christina Leann Appin, Craig Horbinski, Leonidas C. Platanias, Aurora Lopez-Rosas, Yu Han, Irina V. Balyasnikova, MacIej S. Lesniak*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1928-1943
Number of pages16
JournalCancer Immunology Research
Volume7
Issue number12
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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