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

Jingying Zhou; Huanyu Wang; Ting Shu; Jing Wang; Weiqin Yang; Jingqing Li; Lipeng Ding; Man Liu; Hanyong Sun; John Wong; Paul Bo-San Lai; Shun-Wa Tsang; Simon E Ward; King-Lau Chow; Joseph Jao-Yiu Sung; Alfred Sze-Lok Cheng

doi:10.1016/j.isci.2023.107626

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

iScience. 2023 Aug 12;26(10):107626. doi: 10.1016/j.isci.2023.107626. eCollection 2023 Oct 20.

Authors

Jingying Zhou¹, Huanyu Wang¹, Ting Shu¹, Jing Wang¹, Weiqin Yang¹, Jingqing Li¹, Lipeng Ding¹, Man Liu², Hanyong Sun³, John Wong⁴, Paul Bo-San Lai⁴, Shun-Wa Tsang⁵, Simon E Ward⁶, King-Lau Chow⁵, Joseph Jao-Yiu Sung^{7

8}, Alfred Sze-Lok Cheng¹

Affiliations

¹ School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
² Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
⁵ Division of Life Science, Hong Kong University of Science and Technology, Hong Kong SAR 999077, China.
⁶ Medicines Discovery Institute, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK.
⁷ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
⁸ State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.

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 signaling 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.

Keywords: Cancer; Cell biology; Immunology; Microenvironment; Molecular biology.