Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction
Zhen Wang, Fanlian Zeng, Yawen Hu, Xiaoyan Wang, Fulei Zhao, Pei Zhou, Jing Hu, Yuanyuan Xiao, Zhonglan Hu, Mingfeng Guo, Xiaoqiong Wei, Xiao Liu, Nongyu Huang, Jun Zhang, Shuwen Chen, Juan Cheng, Huaping Zheng, Hong Zhou, Qixiang Zhao, Chen Zhang, Yan Hao, Song Zou, Yi-Yue Gui, Jiadong Yu, Linna Gu, Chengcheng Yue, Haozhou Zhang, Wenling Wu, Yifan Zhou, Xikun Zhou, Guobo Shen, Xiu Teng, Jiong Li
Abstract
Abstract 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.