Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis
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AbstractThe liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types. Although a role for cancer cell invasion programs has been well characterized, whether and how liver-intrinsic factors drive metastatic spread is incompletely understood. Here, we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase (CCRK) signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment. Using an inducible liver-specific transgenic model, we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer (CRC) metastasis to the liver, which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and lacking natural killer T (NKT) cells. Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7% (metastatic tumor weights) in the melanoma and CRC models, respectively. Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) signaling to increase the PMN-MDSC-trafficking chemokine C-X-C motif ligand 1 (CXCL1), which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-κB/CXCL1 signaling, which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors. In summary, this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance. Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.
Acceptance Date10/08/2020
All Author(s) ListXuezhen Zeng, Jingying Zhou, Zhewen Xiong, Hanyong Sun, Weiqin Yang, Myth T S Mok, Jing Wang, Jingqing Li, Man Liu, Wenshu Tang, Yu Feng, Hector Kwong-Sang Wang, Shun-Wa Tsang, King-Lau Chow, Philip Chun Yeung, John Wong, Paul Bo-San Lai, Anthony Wing-Hung Chan, Ka Fai To, Stephen Lam Chan, Qiang Xia, Jing Xue, Xiao Chen, Jun Yu, Sui Peng, Joseph Jao-Yiu Sung, Ming Kuang, Alfred Sze-Lok Cheng
Journal nameCellular and Molecular Immunology
Year2021
Month4
Volume Number18
Issue Number4
PublisherSpringer Nature
Pages1005 - 1015
ISSN1672-7681
eISSN2042-0226
LanguagesEnglish-United States

Last updated on 2021-17-06 at 23:39