Abstract:
Oncolytic viruses are an emerging class of cancer immunotherapies, with several agents approved for clinical use. Mammalian reovirus-based therapies are currently being evaluated in numerous clinical trials, commonly in combination with other immunotherapies such as immune checkpoint blockade. As these combinations are designed to augment antitumor immunity, it is increasingly urgent to define how reovirus infection itself shapes tumor–immune interactions. Here, we investigate the immunological consequences of reovirus infection using tumor cell lines, primary human biopsies and clinical datasets. We uncover that reovirus infection induces a marked reduction in surface MHC-I expression on tumor cells, lead to impaired CD8⁺ T-cell-mediated antitumor responses. Mechanistically, we identify that reduced expression of tissue inhibitor of metalloproteinases-1 (TIMP1) is a critical mediator of reovirus-driven MHC-I downregulation. Moreover, disrupting this pathway restores tumor MHC-I expression. Together, these findings uncover an unanticipated immune-modulatory effect of reovirus and provide a mechanistic rationale for optimizing reovirus-based therapies to improve clinical efficacy.
