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

التفاصيل البيبلوغرافية
العنوان:	Myeloid-derived itaconate suppresses cytotoxic CD8 ⁺ T cells and promotes tumour growth.
المؤلفون:	Zhao H; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA., Teng D; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA., Yang L; Department of Chemistry, Princeton University, Princeton, NJ, USA.; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.; Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China., Xu X; Department of Chemistry, Princeton University, Princeton, NJ, USA.; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA., Chen J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Jiang T; Epigenetics Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany., Feng AY; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA., Zhang Y; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Frederick DT; Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA., Gu L; Epigenetics Laboratory, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany., Cai L; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Asara JM; Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA., Pasca di Magliano M; Department of Surgery, University of Michigan, Ann Arbor, MI, USA.; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.; Cancer Biology Program, University of Michigan, Ann Arbor, MI, USA.; Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA.; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Boland GM; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA., Flaherty KT; Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA., Swanson KD; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA., Liu D; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Rabinowitz JD; Department of Chemistry, Princeton University, Princeton, NJ, USA.; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.; Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA., Zheng B; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. bin.zheng@cbrc2.mgh.harvard.edu.
المصدر:	Nature metabolism [Nat Metab] 2022 Dec; Vol. 4 (12), pp. 1660-1673. Date of Electronic Publication: 2022 Nov 14.
نوع المنشور:	Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: Springer Nature Country of Publication: Germany NLM ID: 101736592 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2522-5812 (Electronic) Linking ISSN: 25225812 NLM ISO Abbreviation: Nat Metab Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: Berlin : Springer Nature, [2019]-
مواضيع طبية MeSH:	Neoplasms/metabolism , Myeloid-Derived Suppressor Cells/metabolism, Mice ; Female ; Animals ; CD8-Positive T-Lymphocytes ; Succinates/pharmacology ; Succinates/metabolism ; Tumor Microenvironment
مستخلص:	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. (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
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معلومات مُعتمدة:	P30 CA046592 United States CA NCI NIH HHS; R21 CA227588 United States CA NCI NIH HHS; R01 CA151588 United States CA NCI NIH HHS; R01 CA163591 United States CA NCI NIH HHS; R50 CA232985 United States CA NCI NIH HHS; R01 CA198074 United States CA NCI NIH HHS; DP1 DK113643 United States DK NIDDK NIH HHS; R01 CA219814 United States CA NCI NIH HHS; U01 CA224145 United States CA NCI NIH HHS
المشرفين على المادة:	Q4516562YH (itaconic acid) 0 (Succinates)
تواريخ الأحداث:	Date Created: 20221114 Date Completed: 20221223 Latest Revision: 20240528
رمز التحديث:	20240529
مُعرف محوري في PubMed:	PMC10593361
DOI:	10.1038/s42255-022-00676-9
PMID:	36376563
قاعدة البيانات:	MEDLINE

الوصف
تدمد:	2522-5812
DOI:	10.1038/s42255-022-00676-9