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Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis

Cellular & Molecular Immunology volume 18, pages 1005–1015 (2021)Cite this article

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Abstract

The 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.

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Fig. 3: Depletion of PMN-MDSCs restores hepatic NKT cells and abrogates liver metastasis in CCRK-TG mice.
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Acknowledgements

We acknowledge Prof. Andrew M.L. Chan for his kind gift of the B16F10 melanoma cell line. This project is supported by the University Grants Committee through the Collaborative Research Fund (C4045-18W), Theme-based Research Scheme (T11-706/18-N), General Research Fund (14108219, 14105419), the Li Ka Shing Foundation and the Terry Fox Foundation.

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Authors and Affiliations

  1. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China

    Xuezhen Zeng, Jingying Zhou, Zhewen Xiong, Weiqin Yang, Myth T. S. Mok, Jing Wang, Jingqing Li, Wenshu Tang, Yu Feng & Alfred Sze-Lok Cheng

  2. Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Xuezhen Zeng, Jun Yu, Sui Peng, Joseph Jao-Yiu Sung, Ming Kuang & Alfred Sze-Lok Cheng

  3. Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Xuezhen Zeng & Ming Kuang

  4. Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Xuezhen Zeng & Xiao Chen

  5. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China

    Jingying Zhou, Anthony Wing-Hung Chan & Ka Fai To

  6. Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Hanyong Sun & Qiang Xia

  7. Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Man Liu

  8. Division of Life Science, Hong Kong University of Science and Technology, Hong Kong SAR, China

    Hector Kwong-Sang Wang, Shun-Wa Tsang & King-Lau Chow

  9. Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China

    Philip Chun Yeung, John Wong & Paul Bo-San Lai

  10. State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China

    Ka Fai To

  11. Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China

    Stephen Lam Chan

  12. State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China

    Jing Xue

  13. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

    Jun Yu & Joseph Jao-Yiu Sung

  14. State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China

    Jun Yu & Joseph Jao-Yiu Sung

  15. Clinical Trial Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Sui Peng

  16. Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Ming Kuang

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  1. Xuezhen Zeng
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Contributions

Study concept and design: X.Z., J.Z., and A.S.L.C.; acquisition of data: X.Z., Z.X., H.S., W.Y., M.T.S.M., J.W., J.L., M.L., W.T., Y.F., H.K.S.W., S.W.T., and K.L.C.; analysis and interpretation of the data: X.Z., J.Z., and A.S.L.C.; acquisition of patient specimens: H.S., P.C.Y., J.W., P.B.S.L., A.W.H.C., K.F.T., and Q.X.; drafting of the manuscript: X.Z., J.Z., and A.S.L.C.; critical revision of the manuscript: J.Z., K.L.C., A.W.H.C., K.F.T., S.L.C., J.X., X.C., J.Y., S.P., J.J.Y.S., M.K., and A.S.L.C.; obtained funding: J.Z., J.J.Y.S., M.K., and A.S.L.C.; and study supervision: J.Z. and A.S.L.C.

Corresponding authors

Correspondence to Jingying Zhou or Alfred Sze-Lok Cheng.

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Zeng, X., Zhou, J., Xiong, Z. et al. Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis. Cell Mol Immunol 18, 1005–1015 (2021). https://doi.org/10.1038/s41423-020-00534-2

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