Signal Transduction and Targeted Therapy (Jan 2022)

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

  • 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

DOI
https://doi.org/10.1038/s41392-021-00820-z
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 17

Abstract

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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.