Abstract

Abstract Oncolytic virotherapy aims to potentiate antitumor responses via multiple mechanisms, including direct tumor lysis, increasing immune cell infiltration, modulating innate and adaptive immune interactions, and vascular modification. In an ideal situation, the oncolysis leads to release of tumor antigens and danger signals, to attract immune cells particularly dendritic cells (DC) into the tumor microenvironment (TME) and to recruit functional cytotoxic T lymphocytes (CTL). However, inflammation in the TME also has detrimental effects to promote cancer progression through reducing intratumoral T cell viability, promoting cancer cell proliferation and angiogenesis, and attracting immune suppressive cells. This complex balancing act dictates the outcome of oncolytic virotherapy and is yet fully understood. In this study, we demonstrated that in situ vaccinia virotherapy primarily recruited polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) into the TME where they exhibited strong suppression of T cell effector function in a ROS-dependent way. Single-cell RNA sequencing analysis confirmed the heightened suppressive activity of PMN-MDSC at the transcriptomic level and identified CXCR2 as a therapeutic target expressed on PMN-MDSC. Abrogating PMN-MDSC trafficking by CXCR2-specific small molecule inhibitor during in situ vaccinia virotherapy exhibited enhanced antitumor efficacy in three syngeneic cancer models, through manipulating MDSC and T cell populations in the TME, activating CTL and skewing suppressive TME into an antitumor environment. Our results warrant clinical development of CXCR2 inhibitor in combination with oncolytic virotherapy. Hong Kong Research Grant Council (TRS: T12-703/19-R and T11-709/21-N; CRF: C1134-20G and C7156-20G); Hong Kong Health and Medical Research Fund (HMRF 05162326), the Hong Kong Pneumoconiosis Compensation Fund Board (PCFB).

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