Anti-PD-1 induces M1 polarization in the glioma microenvironment and exerts therapeutic efficacy in the absence of CD8 cytotoxic T cells.

Purpose: Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated inconsistent therapeutic results in patients with glioblastoma (GBM) including those with profound impairments in CD8 T cell effector responses Experimental Design: . We observed a survival benefit in immunocompetent mice with endogenously-arising intracranial glioblastomas after intravenous administration of anti-PD-1. The therapeutic effect of PD-1 administration persisted in mice even after genetic ablation of the CD8 gene (CD8-/-). CD11b+ and Iba1+ monocytes and macrophages were enriched in the glioma microenvironment of the CD8-/- mice Results: The macrophages and microglia assumed a proinflammatory M1 response signature in the setting of anti-PD-1 blockade through the elimination of PD-1-expressing macrophages and microglia in the tumor microenvironment. Anti-PD-1 can inhibit the proliferation of and induce apoptosis of microglia through Ab-dependent cellular cytotoxicity (ADCC), as fluorescently-labeled anti-PD-1 was shown to gain direct access to the glioma microenvironment. Conclusions: Our results show that the therapeutic effect of anti-PD-1 blockade in GBM may be mediated by the innate immune system, rather than by CD8 T cells.