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

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.

• Authors: Yu-Jia Chen, Guan-Nan Li, Xian-Jing Li, Lin-Xing Wei, Min-Jie Fu, Zhou-Li Cheng, Zhen Yang, Gui-Qi Zhu, Xu-Dong Wang, Cheng Zhang, Jin-Ye Zhang, Yi-Ping Sun, Hexige Saiyin, Jin Zhang, Wei-Ren Liu, Wen-Wei Zhu, Kun-Liang Guan, Yue Xiong, Yong Yang, Dan Ye, Lei-Lei Chen
• Journal: Science advances (Sci Adv) Vol. 9 Issue 17 Pg. eadg0654 (04 28 2023) ISSN: 2375-2548 [Electronic] United States
• PMID: 37115931 (Publication Type: Journal Article)

Chemical References

• Irg1 protein, mouse
• Hydro-Lyases

Topics

• Humans
• Animals
• Mice
• Tumor-Associated Macrophages (metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Macrophages (metabolism)
• Immunotherapy
• Neoplasms (genetics, therapy, metabolism)
• Hydro-Lyases (genetics)