An Inflammatory Checkpoint Generated by <i>IL1RN</i> Splicing Offers Therapeutic Opportunity for <i>KRAS</i>-Mutant Intrahepatic Cholangiocarcinoma-Reference-Cited by-同舟云学术

An Inflammatory Checkpoint Generated by IL1RN Splicing Offers Therapeutic Opportunity for KRAS-Mutant Intrahepatic Cholangiocarcinoma

Published:2023-07-24 Issue:10 Volume:13 Page:2248-2269
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Zhang Mao¹^ORCID,Huang Yingying²^ORCID,Pan Jiaomeng¹^ORCID,Sang Chen¹^ORCID,Lin Youpei¹^ORCID,Dong Liangqing¹^ORCID,Shen Xia³^ORCID,Wu Yingcheng¹^ORCID,Song Guohe¹^ORCID,Ji Shuyi³^ORCID,Liu Fen⁴^ORCID,Wang Mengcheng⁴^ORCID,Zheng Yuyan⁵^ORCID,Zhang Sirui²^ORCID,Wang Zefeng²^ORCID,Ren Jianke²^ORCID,Gao Daming⁴^ORCID,Zhou Jian¹⁶^ORCID,Fan Jia¹⁶^ORCID,Wei Wu²⁷⁸^ORCID,Lin Jian³^ORCID,Gao Qiang¹⁶⁹^ORCID

Affiliation:

1. 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.

2. 2CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

3. 3Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China.

4. 4State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.

5. 5Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

6. 6Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

7. 7Lingang Laboratory, Shanghai, China.

8. 8Translational Medicine Institute of Jiangxi, The First Affiliated Hospital of Nanchang University, Jiangxi, China.

9. 9State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.

Abstract

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

Funder

National Natural Science Foundation of China

Science and Technology Commission of Shanghai Municipality

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

Link

https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-23-0282/3349000/cd-23-0282.pdf

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