Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity

• Type of Material: Article
• Authors: Chao Chen, Emory University; Hong Zheng, Emory University; Edwin Horwitz, Emory University; Satomi Ando, Emory University; Koichi Araki, Emory University; Peng Zhao, Emory University; Peng Li, Emory University; Mandy L Ford, Emory University; Rafi Ahmed, Emory University; Cheng-Kui Qu, Emory University
• Language: English
• Date: 2023-12-06
• Publisher: Science
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): https://doi.org/10.1126/sciadv.adf9522
• Title of Journal or Parent Work: Science Advances
• Volume: 9
• Issue: 49
• Start Page: eadf9522
• Grant/Funding Information: This work was supported by the National Institutes of Health grants HL162725, CA275964, and HL130995 (to C.-K.Q.) and a Winship Cancer Institute Invest$ Pilot Grant.
• Keywords: CD8+ effector T cell; protein tyrosine phosphatase; Mitochondria
• Research Categories: Biology, Cell; Health Sciences, Immunology

Abstract

Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection—the utilization of pyruvate, a major mitochondrial substrate derived from glucose—was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.