Enhancing the efficacy of vaccinia-based oncolytic virotherapy by inhibiting CXCR2-mediated MDSC trafficking

Journal of Leukocyte Biology 2023 December 8 [Link]

Zhiwu Tan, Mei Sum Chiu, Ming Yue, Hau Yee Kwok, Man Ho Tse, Yang Wen, Bohao Chen, Dawei Yang, Dongyan Zhou, You-Qiang Song, Kwan Man, Zhiwei Chen

Abstract

Oncolytic virotherapy is an innovative approach for cancer treatment. However, recruitment of myeloid derived suppressor cells (MDSC) into the tumor microenvironment (TME) after oncolysis-mediated local inflammation leads to tumor resistance to the therapy. Using the murine malignant mesothelioma model, we demonstrated that the in-situ vaccinia virotherapy recruited primarily polymorphonuclear MDSC (PMN-MDSC) into the TME where they exhibited strong suppression of cytotoxic T lymphocytes (CTL) in a reactive oxygen species (ROS)-dependent way. Single-cell RNA sequencing analysis confirmed the suppressive profile 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 the vaccinia virotherapy exhibited enhanced antitumor efficacy in three syngeneic cancer models, through increasing CD8+/MDSC ratios 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.