An inflammatory checkpoint generated by IL1RN splicing offers therapeutic opportunity for KRAS mutant intrahepatic cholangiocarcinoma

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  • 作者：Zhang Mao, Huang Yingying, Pan Jiaomeng, Sang Chen, Lin Youpei, Dong Liangqing, Shen Xia, Wu Yingcheng, Song Guohe, Ji Shuyi, Liu Fen, Wang Mengcheng, Zheng Yuyan, Zhang Sirui, Wang Zefeng, Ren Jianke, Gao Daming, Zhou Jian, Fan Jia, Wei Wu, Lin Jian, Gao Qiang
  • 期刊：Cancer Discovery
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KRAS mutations are causally linked to pro-tumor inflammation and identified as driving factors in tumorigenesis. Here, using multi-omics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS mutant iCCA. In KRAS mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant anti-tumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti-PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in KRAS mutant iCCA patients were significantly associated with superior response to anti-PD-1 immunotherapy.

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