Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis

Zhou, Jingying, Wang, Huanyu, Shu, Ting, Wang, Jing, Yang, Weiqin, Li, Jingqing, Ding, Lipeng, Liu, Man, Sun, Hanyong, Wong, John, Lai, Paul Bo-san, Tsang, Shun-Wa, Ward, Simon E. ORCID: https://orcid.org/0000-0002-8745-8377, Chow, King-Lau, Sung, Joseph Jao-yiu and Sze-Lok Cheng, Alfred 2023. Myeloid-intrinsic cell cycle-related kinase drives immunosuppression to promote tumorigenesis. iScience 26 (10) , 107626. 10.1016/j.isci.2023.107626

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Abstract

Massive expansion of immature and suppressive myeloid cells is a common feature of malignant solid tumors. Over-expression of cyclin-dependent kinase 20, also known as cell cycle-related kinase (CCRK), in hepatocellular carcinoma (HCC) correlates with reduced patient survival and low immunotherapy responsiveness. Beyond tumor-intrinsic oncogenicity, here we demonstrated that CCRK is upregulated in myeloid cells in tumor-bearing mice and in patients with HCC. Intratumoral injection of Ccrk-knockdown myeloid-derived suppressor cells (MDSCs) increased tumor-infiltrating CD8+T cells and suppressed HCC tumorigenicity. Using an indel mutant transgenic model, we showed that Ccrk inactivation in myeloid cells conferred a mature phenotype with elevated IL-12 production, driving Th1 responses and CD8+T cell cytotoxicity to reduce orthotopic tumor growth and prolong survival. Mechanistically, CCRK activates STAT3/E4BP4 signalling in MDSCs to acquire immunosuppressive activity through transcriptional IL-10 induction and IL-12 suppression. Taken together, our findings unravel mechanistic insights into MDSC-mediated immunosuppression and offer a therapeutic kinase-target for cancer immunotherapy.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/, Start Date: 2023-08-10
Publisher:	Cell Press
ISSN:	2589-0042
Date of First Compliant Deposit:	15 August 2023
Date of Acceptance:	9 August 2023
Last Modified:	03 Oct 2023 14:55
URI:	https://orca.cardiff.ac.uk/id/eprint/161780

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