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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Science advances - 9(2023), 17 vom: 28. Apr., Seite eadg0654 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Yu-Jia [VerfasserIn] |
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| Links: |
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| Themen: |
EC 4.2.1.- |
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| Anmerkungen: |
Date Completed 01.05.2023 Date Revised 03.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1126/sciadv.adg0654 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM356194930 |
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| 245 | 1 | 0 | |a Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy |
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| 520 | |a 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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| 700 | 1 | |a Li, Xian-Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Lin-Xing |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Min-Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Zhou-Li |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Gui-Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xu-Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jin-Ye |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yi-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Saiyin, Hexige |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Wei-Ren |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Wen-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Kun-Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Lei-Lei |e verfasserin |4 aut | |
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