Polio Virotherapy of Malignant Glioma Engages the Tumor Myeloid Infiltrate and Triggers Global Microglia Activation

Malignant glioma formation involves an abundant inflammatory infiltrate dominated by glioma-associated macrophages and microglia (GAMM). GAMM constitutes a large portion of the glioma mass and tumor microenvironment. They are actively involved in tissue repair and immune surveillance, however in the tumor microenvironment (TME), they are subverted to promote tumor progression. The human poliovirus receptor, hCD155h, is constitutively expressed in members of the mononuclear phagocytic system and is upregulated ectopically in the neoplastic compartment of malignant gliomas (and solid cancers in general). Intratumor treatment with the highly attenuated rhino:poliovirus chimera, PVSRIPO, has a dual effect of releasing neoantigens by oncolysis and activating the GAMM component via sublethal infection, leading to a substantial but transient immune therapy effect. In a phase I clinical trial, PVSRIPO treatment resulted in 21% long-term survival with durable radiographic responses in patients with recurrent glioblastoma (Desjardins et al. New England Journal of Medicine, 2018). Therefore, studying the mechanisms of PVSRIPO immunotherapy in mouse brain tumor models to decipher contributions of viral infection to GAMM vs. malignant cells is critical to improving the therapeutic efficacy in ongoing clinical trials. We recapitulated the clinical trial scenario in an immunocompetent intracerebral mouse tumor model (CT2A-CD155) and obtained baseline and post treatment brain in a time series. Histopathology studies, combined with detailed multiplex IHC/IF and RNAseq were performed on tumor bearing brains. We found the PVSRIPO therapy induced intense engagement of the GAMM infiltrate accompanied by substantial, but transient tumor regression. There were extensive microglia activation and proliferation in adjacent brain parenchyma and even part of the contralateral cortex. This occurred against a backdrop of sustained innate antiviral inflammation and is associated with an induction of the PD-L1 immune checkpoint on GAMM. In contrast to transient antitumor effects observed after PVSRIPO monotherapy, combining PVSRIPO with PD1/PD-L1 blockade led to durable remission. Our work implicates GAMM as active drivers of inflammation and reveals broad neuroinflammatory activation of the CNS-resident myeloid compartment upon polio virotherapy of malignant glioma.