Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Cancer Discov. 2023 Oct 5;13(10):2248-2269. doi: 10.1158/2159-8290.CD-23-0282.
KRAS mutations are causally linked to protumor inflammation and are identified as driving factors in tumorigenesis. Here, using multiomics 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 antitumor 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 patients with KRAS-mutant iCCA were significantly associated with superior response to anti-PD-1 immunotherapy.
This work describes a novel inflammatory checkpoint mediated by IL1RN alternative splicing variants that may serve as a promising basis to develop therapeutic options for KRAS-mutant iCCA and other cancers. This article is featured in Selected Articles from This Issue, p. 2109.
KRAS 突变与促肿瘤炎症有因果关系，被确定为肿瘤发生的驱动因素。在这里，我们使用从大量患者收集的多组学数据表明，KRAS 突变与特定的选择性 mRNA 剪接景观相关，该景观与肝内胆管癌（iCCA）中的髓样炎症有关。然后，我们确定了一种负反馈机制，即由于选择性剪接导致白细胞介素 1 受体拮抗剂（IL1RN）-201/203 的上调赋予了 KRAS 突变型 iCCA 重要的抗炎作用。在 KRAS 突变型 iCCA 小鼠中，IL1RN-201/203 的上调和 anakinra 治疗通过改变中性粒细胞募集和表型引发了显著的抗肿瘤免疫反应。此外，anakinra 治疗与抗 PD-1 治疗协同增强，激活 KRAS 突变型 iCCA 小鼠肿瘤内的 GZMB+CD8+T 细胞。临床上，我们发现 KRAS 突变型 iCCA 患者中高 IL1RN-201/203 水平与对抗 PD-1 免疫治疗的反应明显相关。
这项工作描述了一种由 IL1RN 选择性剪接变体介导的新型炎症检查点，它可能为开发 KRAS 突变型 iCCA 和其他癌症的治疗选择提供有希望的基础。本文是本期精选文章的特色，第 2109 页。
