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

• DOI: 10.1038/s41392-021-00820-z
• Publication Date: 2022-01-20T01:03:37Z
• Authors: Zhen Wang; Fan-lian Zeng; Ya-wen Hu; Xiao-yan Wang; Fu-lei Zhao; Pei Zhou; Jing Hu; Yuan-yuan Xiao; Zhong-lan Hu; Ming-feng Guo; Xiao-qiong Wei; Xiao Liu; Nong-yu Huang; Jun Zhang; Shu-wen Chen; Juan Cheng; Hua-ping Zheng; Hong Zhou; Qi-xiang Zhao; Chen Zhang; Yan Hao; Song Zou; Yi-yue Gui; Jia-dong Yu; Lin-na Gu; Cheng-cheng Yue; Hao-zhou Zhang; Wen-ling Wu; Yi-fan Zhou; Xi-kun Zhou; Guo-bo Shen; Xiu Teng; Jiong Li
• Keywords: 0303 health sciences; QH301-705.5; Carcinogenesis; R; Receptors, Interleukin-1; Mice, Transgenic; Colitis; Article; Neoplasm Proteins; 3. Good health; Mice; 03 medical and health sciences; Medicine; Animals; Biology (General); Colorectal Neoplasms; Interleukin-1; T-Lymphocytes, Cytotoxic

AbstractInterleukin-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.