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.

Immuno-Responsive Gene-1: A mitochondrial gene regulates pathogenic Th17 in CNS autoimmunity mouse model

“…In addition, Irg1 KO mice exhibited disease severity and macrophages lacking Irg1 displayed heightened production of pro-inflammatory cytokines, suggesting that Irg1 impacts the functional states of immune cells as well as involves in EAE pathogenicity. Our results align with previous studies, which showed that macrophages lacking Irg1 exhibited a proinflammatory macrophage phenotype 8,46,47…”

Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides

“…monocytes, macrophages). However, our findings add to a growing body of evidence suggesting that the activity of Acod1 can alter the TME in a fashion that alters ICB sensitivity 44 . In particular, we report here that Acod1 is expressed in both human and mouse cancerous epithelial cells.…”

“…Previous studies have determined that diminished integrin function in epithelial cells during separation from the ECM activates the NFκB signaling pathway 34, 43 . Relatedly, Acod1 expression has previously been found to be regulated by NFκB signaling 44 . Thus, we assessed the contribution of NFκB signaling to the increase in Acod1 levels observed in PRp cells.…”

“…Acod1-mediated ITA can be secreted into the extracellular space 18, 47 , and, despite its hydrophobic nature, can cross the plasma membrane and be utilized by recipient cells 48 . In addition to the known immunomodulatory roles of ITA in macrophages 44 , recent studies have examined a role for ITA in the regulation of T cell proliferation and differentiation 29, 30, 49 . We thus posited that secretion of extracellular ITA by cancer cells expressing Acod1 can result in the inhibition of CD8 + T cells proliferation/activation.…”

Acod1 expression in cancer cells promotes immune evasion through the generation of inhibitory peptides

“… 35 , 45 Relatedly, Acod1 expression has previously been found to be regulated by NF-κB signaling. 46 Thus, we assessed the contribution of NF-κB signaling to the increase in Acod1 levels observed in ECM detachment. Indeed, treatment of detached PRp cells with BAY1170-82, an NF-κB inhibitor, caused a significant downregulation of both Acod1 protein ( Figure 2 E) and Acod1 mRNA expression ( Figure S3C ).…”