Acetyl-CoA carboxylase obstructs CD8 + T cell lipid utilization in the tumor microenvironment.

Autor:	Hunt EG; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Hurst KE; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Riesenberg BP; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Kennedy AS; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Gandy EJ; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Andrews AM; Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA., Del Mar Alicea Pauneto C; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Ball LE; Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA., Wallace ED; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Gao P; Department of Medicine, Metabolomics Core Facility, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA., Meier J; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Serody JJ; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Coleman MF; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Thaxton JE; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA. Electronic address: jess_thaxton@med.unc.edu.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 May 07; Vol. 36 (5), pp. 969-983.e10. Date of Electronic Publication: 2024 Mar 14.
DOI:	10.1016/j.cmet.2024.02.009
Abstrakt:	The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor-infiltrating T cells (TILs), hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control. However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. We reveal that the solid TME imposes perpetual acetyl-coenzyme A (CoA) carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, which sustains cancer control. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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