Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy
Menée à l'aide de lignées cellulaires, de modèles murins, d'échantillons sanguins et tumoraux provenant de patients ainsi que de données transcriptomiques du projet "The Cancer Genome Atlas" portant sur 18 types de cancer, cette étude met en évidence l'intérêt de cibler l'expression du gène IRG1 pour inhiber la fonction immunosuppressive des macrophages associés à la tumeur et améliorer l'efficacité des immunothérapies
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.
Science Advances 2022