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

Hongyun Zhao, Da Teng, Lifeng Yang, Xincheng Xu, Jiajia Chen, Tengjia Jiang, Austin Y. Feng, Yaqing Zhang, Dennie T. Frederick, Lei Gu, Li Cai, John M. Asara, Marina Pasca di Magliano, Genevieve M. Boland, Keith T. Flaherty, Kenneth D. Swanson, David Liu, Joshua D. Rabinowitz, Bin Zheng

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1660-1673
Number of pages14
JournalNature Metabolism
Volume4
Issue number12
DOIs
StatePublished - Dec 2022

All Science Journal Classification (ASJC) codes

  • Physiology (medical)
  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology

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