免疫系统
细胞毒性T细胞
生物
CD8型
癌症研究
免疫检查点
免疫
代谢物
髓样
封锁
细胞生物学
免疫疗法
免疫学
生物化学
体外
受体
作者
Hongyun Zhao,Da Teng,Lifeng Yang,Xincheng Xu,Jiajia Chen,Teng-Jia Jiang,Austin Y. Feng,Yaqing Zhang,Dennie T. Frederick,Lei Gu,Cai Li,John M. Asara,Marina Pasca di Magliano,Genevieve M. Boland,Keith T. Flaherty,Kenneth D. Swanson,David Liu,Joshua D. Rabinowitz,Bin Zheng
标识
DOI:10.1038/s42255-022-00676-9
摘要
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.
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