2. Academic Validation
  3. Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy

  • Sci Adv. 2023 Apr 28;9(17):eadg0654. doi: 10.1126/sciadv.adg0654.
Yu-Jia Chen 1,  Guan-Nan Li 1,  Xian-Jing Li 2,  Lin-Xing Wei 1,  Min-Jie Fu 3,  Zhou-Li Cheng 1,  Zhen Yang 1,  Gui-Qi Zhu 4,  Xu-Dong Wang 5,  Cheng Zhang 1,  Jin-Ye Zhang 1,  Yi-Ping Sun 1,  Hexige Saiyin 6,  Jin Zhang 5 7,  Wei-Ren Liu 4,  Wen-Wei Zhu 8,  Kun-Liang Guan 9,  Yue Xiong 10,  Yong Yang 2,  Dan Ye 1 8,  Lei-Lei Chen 1
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University; Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology); Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education); Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 3 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
  • 4 Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Shanghai, China.
  • 5 Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow for Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 6 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
  • 7 Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, Zhejiang Province, China.
  • 8 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 9 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA.
  • 10 Cullgen Inc., 12671 High Bluff Drive, San Diego, CA 92130, USA.
PMID: 37115931 DOI: 10.1126/sciadv.adg0654
Abstract

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in Cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8+ T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti-PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1-deficient macrophages represent a potent cell therapy strategy for Cancer treatment even in pancreatic tumors that are resistant to T cell-based immunotherapy.

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