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

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 tum...

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Published in:Science advances Vol. 9; no. 17; p. eadg0654
Main Authors: Chen, Yu-Jia, Li, Guan-Nan, Li, Xian-Jing, Wei, Lin-Xing, Fu, Min-Jie, Cheng, Zhou-Li, Yang, Zhen, Zhu, Gui-Qi, Wang, Xu-Dong, Zhang, Cheng, Zhang, Jin-Ye, Sun, Yi-Ping, Saiyin, Hexige, Zhang, Jin, Liu, Wei-Ren, Zhu, Wen-Wei, Guan, Kun-Liang, Xiong, Yue, Yang, Yong, Ye, Dan, Chen, Lei-Lei
Format: Journal Article
Language:English
Published: United States American Association for the Advancement of Science 28.04.2023
Subjects:
Animals
Biomedicine and Life Sciences
Cancer
CD8-Positive T-Lymphocytes - metabolism
Humans
Hydro-Lyases - genetics
Immunology
Immunotherapy
Macrophages - metabolism
Mice
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - therapy
SciAdv r-articles
Tumor-Associated Macrophages - metabolism
ISSN:2375-2548, 2375-2548
Online Access:Get full text
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Summary: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. Targeting IRG1 skews tumor associated macrophages (TAMs) into anti-tumor mode and enhances responses to anti-PD-(L)1 immunotherapy.
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These authors contributed equally to this work.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adg0654