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

Elizabeth G Hunt; Katie E Hurst; Brian P Riesenberg; Andrew S Kennedy; Evelyn J Gandy; Alex M Andrews; Coral Del Mar Alicea Pauneto; Lauren E Ball; Emily D Wallace; Peng Gao; Jeremy Meier; John J Serody; Michael F Coleman; Jessica E Thaxton

doi:10.1016/j.cmet.2024.02.009

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

Cell Metab. 2024 May 7;36(5):969-983.e10. doi: 10.1016/j.cmet.2024.02.009. Epub 2024 Mar 14.

Authors

Affiliations

¹ 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.
² Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
³ Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
⁴ 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.
⁵ Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA.
⁶ Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁷ Department of Medicine, Metabolomics Core Facility, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁸ 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.
⁹ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁰ 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.

PMID: 38490211
DOI: 10.1016/j.cmet.2024.02.009

Abstract

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.

Keywords: T cell; endoplasmic reticulum; immunotherapy; lipid; metabolism; mitochondria; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Acetyl-CoA Carboxylase* / metabolism
Animals
CD8-Positive T-Lymphocytes* / immunology
CD8-Positive T-Lymphocytes* / metabolism
Cell Line, Tumor
Fatty Acids / metabolism
Female
Humans
Lipid Metabolism*
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Mice
Mice, Inbred C57BL
Mitochondria / metabolism
Tumor Microenvironment*

Substances

Acetyl-CoA Carboxylase
Fatty Acids