Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction

• Published in: Signal transduction and targeted therapy Vol. 7; no. 1; pp. 19 - 17
• Main Authors: Wang, Zhen, Zeng, Fan-lian, Hu, Ya-wen, Wang, Xiao-yan, Zhao, Fu-lei, Zhou, Pei, Hu, Jing, Xiao, Yuan-yuan, Hu, Zhong-lan, Guo, Ming-feng, Wei, Xiao-qiong, Liu, Xiao, Huang, Nong-yu, Zhang, Jun, Chen, Shu-wen, Cheng, Juan, Zheng, Hua-ping, Zhou, Hong, Zhao, Qi-xiang, Zhang, Chen, Hao, Yan, Zou, Song, Gui, Yi-yue, Yu, Jia-dong, Gu, Lin-na, Yue, Cheng-cheng, Zhang, Hao-zhou, Wu, Wen-ling, Zhou, Yi-fan, Zhou, Xi-kun, Shen, Guo-bo, Teng, Xiu, Li, Jiong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.01.2022; Nature Publishing Group
• Subjects: 631/250/2152; 631/67/327; 631/67/580; Animals; Apoptosis; Cancer; Cancer Research; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - immunology; CD8 antigen; Cell Biology; Cell culture; Cell migration; Cell proliferation; Cell-mediated immunity; Colitis; Colitis - genetics; Colitis - immunology; Colitis - pathology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Cytokines; Cytotoxicity; Immunosurveillance; Inflammatory bowel disease; Interleukin 1; Interleukin 18; Interleukin-1 - genetics; Interleukin-1 - immunology; Internal Medicine; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Transgenic; Mutagenesis; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Oncology; Pathology; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - immunology; T-Lymphocytes, Cytotoxic - immunology; Therapeutic targets; Transgenic mice; Tumors
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-021-00820-z

Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8 + T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18–induced proliferation and effector function of CD8 + T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8 + T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.