Myeloid cell-cycle-related-kinase drives tumor immunosuppression in hepatocellular carcinoma

Abstract

Abstract Myeloid-derived suppressor cell (MDSC) comprises a heterogeneous population of immature myeloid cells featured by potent immunosuppression. We have uncovered a significant role of hepatoma-intrinsic cyclin-dependent-kinase 20 (CDK20), or cell-cycle-related-kinase (CCRK) in promoting tumor progression and immunotherapy resistance in hepatocellular carcinoma (HCC). As emerging evidence has highlighted the importance of immune cell intrinsic CDKs, we further explored the potentials of CCRK expressions and functions in different immune cells from HCC-bearing mice and patients. Of note, we uncovered specific CCRK overexpression in MDSCs but not lymphocytes, which functioned in regulating MDSC proliferation, immunosuppression, and differentiation. Intratumoral injection of bone-marrow-derived MDSCs with Ccrkknockdown resulted in impaired tumorigenicity, accompanied with increased CD8 +T cell responses. Mechanistically, myeloid CCRK upregulation was functional associated with IL-6-mediated MDSC expansion and immunosuppression. Inhibition of myeloid CCRK in turn suppressed STAT3 to revert E4-binding protein 4-dependent transcriptional alterations. Using a transgenic mouse bearing Ccrk-indel mutation (Ccrkindel/indel), we found that impaired Ccrksignal reprogramed the pro-tumoral MDSCs into an antitumoral phenotype, resulting in suppression of tumor growth in our established HCC orthotopic mouse models. As we also showed CCRK overexpression in HCC patient-derived MDSCs, the findings of our study not only unravel mechanistic insights in MDSC maintenance and immunosuppression, but also offer a novel therapeutic kinase-target in HCC therapies. The project is supported by RGC/GRF14108219. Supported by grants from general research fund (GRF)/research grants council (RGC) of Hong Kong, 14108219.