Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth

The tumour microenvironment possesses mechanisms that suppress anti-tumour immunity. Itaconate is a metabolite produced from the Krebs cycle intermediate cis-aconitate by the activity of immune-responsive gene 1 (IRG1). While it is known to be immune modulatory, the role of itaconate in anti-tumour immunity is unclear. Here, we demonstrate that myeloid-derived suppressor cells (MDSCs) secrete itaconate that can be taken up by CD8(+) T cells and suppress their proliferation, cytokine production and cytolytic activity. Metabolite profiling, stable-isotope tracing and metabolite supplementation studies indicated that itaconate suppressed the biosynthesis of aspartate and serine/glycine in CD8(+) T cells to attenuate their proliferation and function. Host deletion of Irg1 in female mice bearing allografted tumours resulted in decreased tumour growth, inhibited the immune-suppressive activities of MDSCs, promoted anti-tumour immunity of CD8(+) T cells and enhanced the anti-tumour activity of anti-PD-1 antibody treatment. Furthermore, we found a significant negative correlation between IRG1 expression and response to PD-1 immune checkpoint blockade in patients with melanoma. Our findings not only reveal a previously unknown role of itaconate as an immune checkpoint metabolite secreted from MDSCs to suppress CD8(+) T cells, but also establish IRG1 as a myeloid-selective target in immunometabolism whose inhibition promotes anti-tumour immunity and enhances the efficacy of immune checkpoint protein blockade. Itaconate is a metabolite with immune-modulatory effects in myeloid cells. In this study, Zhao, Teng et al. report an additional role for itaconate in CD8(+) T cells, with implications for immune surveillance and anti-tumour immunity.

Automated summary

This study reveals that itaconate, produced by myeloid-derived suppressor cells (MDSCs), acts as an immune checkpoint metabolite to suppress CD8(+) T cells. Inhibition of IRG1 may enhance anti-tumour immunity and improve the efficacy of immune checkpoint blockade. These findings have implications for understanding immune surveillance and developing new strategies for cancer treatment.