Myeloid-derived suppressor cells inhibit the replication of oncolytic virus by reducing intratumoral arginine levels

Oncolytic virotherapy uses replication-competent viruses to treat various solid tumors. While much of the clinical efficacy of oncolytic virotherapy is mediated by anti-tumor T cell responses, most of these therapies still rely on the <i>in vivo</i> replication of the viral agents within infected tumor cells. Understanding the fundamental mechanisms that govern this replication therefore remains essential to the clinical application of these therapies. As viruses, oncolytic agents rely entirely on host metabolites and resources for their propagation. To address this gap in knowledge, we asked which cells impacted the intratumoral replication of oncolytic myxoma virus during treatment of B16F10 melanomas. Our results demonstrate that myxoma replication is potently restricted by the presence of intratumoral arginase-1⁺ myeloid-derived suppressor cells, which prevent the spread of oncolytic infection by catabolizing intratumoral arginine supplies. Additionally, either pharmacological depletion of these cells or genetic ablation of their arginase-1 expression markedly improves intratumoral myxoma infection and enhances the therapeutic efficacy of viruses. Collectively, these results suggest that the clinical application of oncolytic viruses is likely to be impacted by the unique metabolic state of the tumor microenvironment and that myeloid-derived suppressor cell-mediated depression of arginine within tumors may play a critical role in suppressing these treatments.