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

Authors :
Tan, Zhiwu
Chiu, Mei Sum
Yue, Ming
Kwok, Hau Yee
Tse, Man Ho
Wen, Yang
Chen, Bohao
Yang, Dawei
Zhou, Dongyan
Song, You-Qiang
Man, Kwan
Chen, Zhiwei
Source :
Journal of Leukocyte Biology; Apr2024, Vol. 115 Issue 4, p633-646, 14p
Publication Year :
2024

Abstract

Oncolytic virotherapy is an innovative approach for cancer treatment. However, recruitment of myeloid-derived suppressor cells (MDSCs) 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 MDSCs (PMN-MDSCs) into the TME, where they exhibited strong suppression of cytotoxic T lymphocytes in a reactive oxygen species–dependent way. Single-cell RNA sequencing analysis confirmed the suppressive profile of PMN-MDSCs at the transcriptomic level and identified CXCR2 as a therapeutic target expressed on PMN-MDSCs. Abrogating PMN-MDSC trafficking by CXCR2-specific small molecule inhibitor during the vaccinia virotherapy exhibited enhanced antitumor efficacy in 3 syngeneic cancer models, through increasing CD8<superscript>+</superscript>/MDSC ratios in the TME, activating cytotoxic T lymphocytes, and skewing suppressive TME into an antitumor environment. Our results warrant clinical development of CXCR2 inhibitor in combination with oncolytic virotherapy. Vaccinia virotherapy–recruited polymorphonuclear myeloid-derived suppressor cells exhibited strong suppressive function in an reactive oxygen species–dependent way, and pharmacologic CXCR2 inhibition selectively abrogated polymorphonuclear myeloid-derived suppressor cell–mediated immunosuppression and activated cytotoxic T lymphocytes to retard tumor growth. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
07415400
Volume :
115
Issue :
4
Database :
Complementary Index
Journal :
Journal of Leukocyte Biology
Publication Type :
Academic Journal
Accession number :
177205073
Full Text :
https://doi.org/10.1093/jleuko/qiad150