An Inflammatory Checkpoint Generated by IL1RN Splicing Offers Therapeutic Opportunity for KRAS-Mutant Intrahepatic Cholangiocarcinoma
Related Experiment Video
Updated: Jul 22, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Mao Zhang1, Yingying Huang2, Jiaomeng Pan1
1Department 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.
Abstract:
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.
Significance:
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.
Insights
KRAS mutations in intrahepatic cholangiocarcinoma (iCCA) drive inflammation. A novel IL1RN splicing variant acts as an anti-inflammatory checkpoint, enhancing immune response and improving immunotherapy outcomes in KRAS-mutant iCCA.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- KRAS mutations are key drivers of tumorigenesis and protumor inflammation.
- Intrahepatic cholangiocarcinoma (iCCA) with KRAS mutations exhibits a distinct inflammatory profile.
- Alternative mRNA splicing plays a role in cancer development and immune response.
Purpose of the Study:
- To investigate the link between KRAS mutations, alternative splicing, and myeloid inflammation in iCCA.
- To identify novel mechanisms of immune regulation in KRAS-mutant iCCA.
- To explore therapeutic strategies targeting inflammatory pathways in iCCA.
Main Methods:
- Multiomics data analysis from a large patient cohort.
- In vivo studies using KRAS-mutant iCCA mouse models.
- Assessment of immune cell recruitment, phenotypes, and therapeutic responses.
Main Results:
- KRAS mutation in iCCA is associated with a unique alternative splicing landscape linked to myeloid inflammation.
- Upregulation of IL1RN-201/203 via alternative splicing exerts anti-inflammatory effects in KRAS-mutant iCCA.
- IL1RN-201/203 and anakinra treatment promote antitumor immunity and synergize with anti-PD-1 therapy.
- High IL1RN-201/203 levels correlate with better anti-PD-1 immunotherapy response in patients.
Conclusions:
- Alternative splicing of IL1RN creates an inflammatory checkpoint in KRAS-mutant iCCA.
- Targeting this IL1RN-mediated pathway, including anakinra, can enhance antitumor immunity.
- This finding offers a potential therapeutic strategy for KRAS-mutant iCCA and other cancers.
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