TY - JOUR
T1 - Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth
AU - Zhao, Hongyun
AU - Teng, Da
AU - Yang, Lifeng
AU - Xu, Xincheng
AU - Chen, Jiajia
AU - Jiang, Tengjia
AU - Feng, Austin Y.
AU - Zhang, Yaqing
AU - Frederick, Dennie T.
AU - Gu, Lei
AU - Cai, Li
AU - Asara, John M.
AU - Pasca di Magliano, Marina
AU - Boland, Genevieve M.
AU - Flaherty, Keith T.
AU - Swanson, Kenneth D.
AU - Liu, David
AU - Rabinowitz, Joshua D.
AU - Zheng, Bin
N1 - Funding Information:
We thank Emily Robitschek and members of the Zheng Laboratory for helpful discussion on the manuscript. This work is supported by US National Institutes of Health (NIH, nos. R21CA227588 and R01CA219814), the Melanoma Research Alliance, the Elsa U. Pardee Foundation and funds from MGH (to B.Z.); and by NIH (nos. R01CA163591 and DP1DK113643) and Stand Up to Cancer (no. SU2CAACR-DT-20-16) (to J.D.R.). Y.Z. is funded by NCI-R50CA232985. M.P.M. is supported by NIH/NCI grant nos. R01CA151588, R01CA198074 and U01CA-224145 and by the University of Michigan Cancer Center Support Grant (no. NCI P30CA046592).
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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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U2 - 10.1038/s42255-022-00676-9
DO - 10.1038/s42255-022-00676-9
M3 - Article
C2 - 36376563
AN - SCOPUS:85141975699
SN - 2522-5812
VL - 4
SP - 1660
EP - 1673
JO - Nature Metabolism
JF - Nature Metabolism
IS - 12
ER -