PD-1 blockade activates conventional CD4 T cells and the innate immune response during glioblastoma eradication

Abstract

Abstract Blockade of immune cell co-inhibitory receptor PD-1 using monoclonal antibodies enables anti-tumor immune responses in various solid tumors and lymphoid malignancies. Our laboratory previously demonstrated PD-1 blockade elicits an anti-tumor immune response resulting in tumor rejection and long-term survival in approximately 50% of mice with an orthotopic GL261 glioblastoma, despite lacking a corresponding accumulation of CD8+ cytotoxic T cell in the tumor or draining lymph nodes. In this investigation, we evaluated the role of conventional CD4+ T cells and the innate immune response in PD-1 mediated anti-glioma immunity using multiplex technologies for immunohistochemistry and flow cytometry. In response to PD-1 monotherapy, intratumoral CD4 T cells expressed significantly elevated levels of proteins required for T cell proliferation, activation, and effector function. CD4 T cell activation was accompanied by the classical activation and M1 polarization of resident microglia and tumor-infiltrating macrophages, including down-regulation of PD-L1 and up-regulation of MHC class II surface expression. We also demonstrated that depletion of either CD4 or CD8 T cells was sufficient to completely ablate anti-PD-1-mediated tumor eradication and long-term survival. Our data suggests CD4 T cells and myeloid cells may play a prominent role in the eradication of glioblastoma by PD-1 blockade.