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- Title
Pharmacologic inhibition of IL11/STAT3 signaling increases MHC-I expression and T cell infiltration.
- Authors
Xiong, Wenjun; Chen, Yuehong; Zhang, Chaoting; Li, Jin; Huang, Haipeng; Zhu, Yu; Deng, Guangxu; Cheng, Junhong; Lin, Yixiong; Shi, Zhimin; Mou, Tingyu
- Abstract
Background: Recent studies have discovered an emerging role of IL11 in various colitis-associated cancers, suggesting that IL11 mainly promotes tumor cell survival and proliferation in regulating tumorigenesis. Herein we aimed to reveal a novel function of IL-11 through STAT3 signaling in regulating tumor immune evasion. Methods: AOM/DSS model in Il11−/− and Apcmin/+/Il11−/− mice were used to detect tumor growth and CD8+ T infiltration. STAT1/3 phosphorylation and MHC-I, CXCL9, H2-K1 and H2-D1 expression were detected in MC38 cells and intestine organoids treated with/without recombinant IL11 to explore effect of IL11/STAT3 signaling, with IL11 mutein used to competitively inhibit IL11 and rescue inhibited STAT1 activation. Correlation between IL11 and CD8+ T infiltration was analyzed using TIMER2.0 website. IL11 expression and survival prognosis was analyzed in clinical data of patient cohort from Nanfang Hospital. Results: IL11 is highly expressed in CRC and indicates unfavorable prognosis. IL11 knockout increased CD8+ T cell infiltration and reduced intestinal and colon formation. Tumors were significantly suppressed while MHC-I and CXCL9 expression for CD8+ T infiltration were remarkably increased in the tumor tissues of Apcmin/+/Il11−/− mice or Il11−/− mice induced by AOM/DSS. IL11/STAT3 signaling downregulated MHC-I and CXCL9 by inhibiting IFNγ-induced STAT1 phosphorylation. IL11 mutein competitively inhibit IL11 to upregulate CXCL9 and MHC-I in tumor and attenuated tumor growth. Conclusions: This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.
- Subjects
T cell receptors; T cells; TUMOR growth; COLON cancer; CELL survival
- Publication
Journal of Translational Medicine, 2023, Vol 21, Issue 1, p1
- ISSN
1479-5876
- Publication type
Article
- DOI
10.1186/s12967-023-04079-6