Myeloid-Derived Suppressive Cells Promote B cell–Mediated Immunosuppression via Transfer of PD-L1 in Glioblastoma

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 the GBM microenvironment in both preclinical models and clinical samples. Forty percent of GBM patients (n ¼ 60) scored positive for B-cell tumor infiltration. Human and mouse GBM-associated Bregs were characterized by immunosuppressive activity toward activated CD8 þ 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 ¼ 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 þ 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.See related Spotlight on p. 1902

Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer

“…In MM patients, Breg survival was enhanced through MM cell-mediated inhibition of Breg apoptosis in the bone marrow (45). Similarly, breast cancer cells produced metabolites of the 5-lipoxygenase pathway to activate the peroxisome proliferator-activated receptor a (PPARa) in B cells, resulting in tBreg generation; unsurprisingly, inactivation of PPARa prevented tBreg-mediated cancer escape (79). In mice bearing B16-F10 melanoma, T2-MZP Bregs were specifically accumulated in TDLNs (32).…”

Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas

“…Myeloid-derived suppressor cells (MDSCs) are known to act as major immunosuppressive cells within the GBM microenvironment. MDSCs induce B cell-mediated immunosuppression, perhaps inhibiting the effective response to oncolytic viruses armed with immunomodulatory transgenes 95 . In addition, the blood-brain barrier (BBB) limits the delivery of viral vectors, greatly compromising their oncolytic efficacy 25 .…”

Immunotherapies and Metastatic Cancers: Understanding Utility and Predictivity of Human Immune Cell Engrafted Mice in Preclinical Drug Development

“…Patients with prostate cancer bone metastasis have high levels of functional Tregs in the bone marrow, causing the immunosuppressive TME [12]. Regulatory B cells (Bregs) can promote immunosuppressive microenvironment even further by converting CD4+ T cells into Tregs [13,14] and inducing myeloid cells to become immunosuppressive by increasing expression of PD-L1 and production of immunosuppressive cytokines such as transforming growth factor β (TGFβ) and IL-10 [15]. Furthermore, tumor-associated regulatory B cells are needed for TGFβ-dependent pro-metastatic function of myeloid-derived suppressor cells (MDSCs) [16].…”