Abstract 400: Targeting myeloid cell-cycle related kinase signaling amplifies anti-tumor T cell responses via inducing myeloid derived suppressor cell differentiation
Authors: Zhou Jingying , Cheng Alfred Sze Lok 
Published: September 2020

Key words: CDK20, E4BP4, MDSC, Immunosuppression, T cell immunity The breakthrough in understanding the inhibition of negative immune regulation has paved way for cancer immunotherapy. The immune-checkpoint blockade (ICB) therapy has produced promising and yet modest objective response rates in some solid cancers such as hepatocellular

carcinoma (HCC), which have been attributable to the strong immunosuppressive tumor microenvironment (TME). Accumulating evidence has demonstrated that myeloid-derived

suppressor cell (MDSC), an immature myeloid population with potent T cell-suppressive activity, is remarkably associated with poor prognosis and ICB resistance of cancer patients. While targeting MDSC can blunt T cell activity, new approach is directed towards driving differentiation of MDSC into antigen presentation cell crucial for T cell priming and activation. Therefore, decoding the molecular pathways that sustain the immunosuppressive MDSCs will be instrumental in deriving strategies for greater anti-tumor immune responses. Given their pivotal roles in cell cycle and transcriptional regulation, deregulation of cyclin-dependent kinases (CDKs) has become a hallmark of several cancer types. We have recently shown that hepatoma-intrinsic CDK20, or more commonly known as cell cycle-related kinase (CCRK), mitigates anti-tumor T cell responses by expanding MDSCs within TME, while tumoral CCRK depletion diminishes MDSC-mediated immunosuppression leading to improved ICB efficacy. As emerging evidence highlights the key roles of CDKs in immune cell signaling and identity, our new findings from tumor-bearing mice and healthy human blood-derived cell models uncovered specific over-expression of CCRK in MDSCs but not lymphocytes. Notably, blockade of MDSC-intrinsic CCRK induced its differentiation into mature macrophage which amplified T cell responses in vitro and in vivo, resulting in reduced tumorigenicity. Mechanistically, CCRK inhibition suppressed signal transducer and activator of transcription 3 (STAT3) signaling to revert E4-binding protein 4 (E4BP4)-dependent interleukin-10 (IL-10)/IL-12 imbalance and arginase I

expression for maintenance of immunosuppression. As we also showed CCRK over-expression in HCC patient-derived MDSCs, the findings of this study not only unravel mechanistic insights in MDSC maintenance and differentiation, but also offer a novel therapeutic kinase-target to resolve ICB resistance, thereby conferring durable eradication of solid tumors.

Acknowledgement: This project was supported by the University Grants Committee through the General Research Fund 14108219 and the Collaborative Research Fund C4045-18W.

The authors declare no conflict of interests.

Citation Format: Jingying Zhou, Alfred Sze Lok Cheng. Targeting myeloid cell-cycle related kinase signaling amplifies anti-tumor T cell responses via inducing myeloid derived suppressor cell differentiation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 400.