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

被引:29
|
作者
Zeng, Xuezhen [1 ,2 ,3 ,4 ]
Zhou, Jingying [1 ,5 ]
Xiong, Zhewen [1 ]
Sun, Hanyong [6 ]
Yang, Weiqin [1 ]
Mok, Myth T. S. [1 ]
Wang, Jing [1 ]
Li, Jingqing [1 ]
Liu, Man [7 ]
Tang, Wenshu [1 ]
Feng, Yu [1 ]
Wang, Hector Kwong-Sang [8 ]
Tsang, Shun-Wa [8 ]
Chow, King-Lau [8 ]
Yeung, Philip Chun [9 ]
Wong, John [9 ]
Lai, Paul Bo-San [9 ]
Chan, Anthony Wing-Hung [5 ]
To, Ka Fai [5 ,10 ]
Chan, Stephen Lam [11 ]
Xia, Qiang [6 ]
Xue, Jing [12 ]
Chen, Xiao [4 ]
Yu, Jun [2 ,13 ,14 ]
Peng, Sui [2 ,15 ]
Sung, Joseph Jao-Yiu [2 ,13 ,14 ]
Kuang, Ming [2 ,3 ,16 ]
Cheng, Alfred Sze-Lok [1 ,2 ]
机构
[1] Chinese Univ Hong Kong, Sch Biomed Sci, Sha Tin, Hong Kong, Peoples R China
[2] Sun Yat Sen Univ, Affiliated Hosp 1, Inst Precis Med, Guangzhou, Peoples R China
[3] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Liver Surg, Guangzhou, Peoples R China
[4] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Pharm, Guangzhou, Peoples R China
[5] Chinese Univ Hong Kong, Dept Anat & Cellular Pathol, Sha Tin, Hong Kong, Peoples R China
[6] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Liver Surg, Shanghai, Peoples R China
[7] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Peoples R China
[8] Hong Kong Univ Sci & Technol, Div Life Sci, Hong Kong, Hong Kong, Peoples R China
[9] Chinese Univ Hong Kong, Dept Surg, Sha Tin, Hong Kong, Peoples R China
[10] Chinese Univ Hong Kong, State Key Lab Translat Oncol, Sha Tin, Hong Kong, Peoples R China
[11] Chinese Univ Hong Kong, Dept Clin Oncol, Sha Tin, Hong Kong, Peoples R China
[12] Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Stem Cell Res Ctr, Ren Ji Hosp,Sch Med,Shanghai Canc Inst, Shanghai, Peoples R China
[13] Chinese Univ Hong Kong, Dept Med & Therapeut, Sha Tin, Hong Kong, Peoples R China
[14] Chinese Univ Hong Kong, State Key Lab Digest Dis, Sha Tin, Hong Kong, Peoples R China
[15] Sun Yat Sen Univ, Affiliated Hosp 1, Clin Trial Unit, Guangzhou, Peoples R China
[16] Sun Yat Sen Univ, Affiliated Hosp 1, Canc Ctr, Guangzhou, Peoples R China
关键词
Cell cycle related kinase; liver metastasis; liver immune microenvironment; myeloid-derived suppressor cell; natural killer T cell; SUPPRESSOR-CELLS; INHIBITION; SURVIVAL; GENE;
D O I
10.1038/s41423-020-00534-2
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 inCCRKtransgenic 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-kappa B) 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 inCCRKtransgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-kappa B/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.
引用
收藏
页码:1005 / 1015
页数:11
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