Abstract 1485: Hepatic cell cycle-related kinase shapes a metastatic-prone liver microenvironment via crosstalk between myeloid-derived suppressor cell and natural killer T cell

Abstract

Abstract Metastasis is a prominent cause of cancer-related death governed by both cancer cell-intrinsic mechanisms and extrinsic microenvironment. Clinical observations demonstrated liver as a common metastatic site for various cancers, which may be due to its immune tolerant environment. Myeloid-derived suppressor cell (MDSC) is a heterogeneous cell population of immature myeloid cells that contribute to the formation of a favorable metastatic environment partially via suppression of immune effector cells. However, the underlying mechanisms in liver tropism of tumor metastasis remain poorly understood. We have previously discovered that cell cycle-related kinase (CCRK) can promote primary hepatocellular carcinoma (HCC) development via MDSCs (Gut 2018; Nat Commun accepted). Here we hypothesize that the accumulation of hepatic MDSCs induced by CCRK may contribute to the formation of a favorable metastatic liver microenvironment. By the construction of a liver-specific CCRK inducible transgenic (TG) mouse model by a Cre/loxP system, induction of CCRK expression by tamoxifen injection could increase CD11b+Gr-1+Ly6G+Ly6Clow polymorphonuclear (PMN)-MDSCs liver accumulation specifically in male mice with upregulated Cxcl1 and Gcsf expression. Intrahepatic injection of a mouse hepatoma cell line Hep1-6 in male TG mice developed larger tumors compared to control and positively associated with increased PMN-MDSCs levels in liver. Moreover, the tumorigenicity was abolished by PMN-MDSC depletion. Notably, intrasplenic injection of a mouse melanoma cell line B16F10 exhibited increased level of liver-infiltrating PMN-MDSCs and enhanced liver metastasis in male TG mice compared to control mice. Moreover, depletion of PMN-MDSCs suppressed metastasis in liver. Mechanistically, anti-tumor NKT cells, rather than NK cells and CD8+T cells, were negatively correlated with tumor weight and MDSC proportion, indicating the potential crosstalk between MDSC and NKT in liver metastasis. Our findings suggest that hepatic CCRK expression create a tumor growth- and metastasis-supportive liver microenvironment via enhancing immunosuppression. Additional colorectal cancer metastasis models will be evaluated in our established TG mice. Moreover, the roles and underlying mechanisms of CCRK-PMN-MDSC interactions in the establishment of liver metastasis await further investigation. This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309. Citation Format: Xuezhen ZENG, Jingying Zhou, Zhewen Xiong, Hanyong Sun, Weiqin Yang, Wenshu Tang, Yu Feng, Alfred Sze-Lok Cheng. Hepatic cell cycle-related kinase shapes a metastatic-prone liver microenvironment via crosstalk between myeloid-derived suppressor cell and natural killer T cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1485.