CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing

Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2302878120. doi: 10.1073/pnas.2302878120. Epub 2023 Sep 18.

Abstract

Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell-derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.

Keywords: cancer metabolism; carnitine palmitoyltransferase 1A; cellular immunotherapy; fatty acid oxidation; therapeutic resistance.

Publication types

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

MeSH terms

  • Carnitine O-Palmitoyltransferase* / genetics
  • Cytotoxicity, Immunologic
  • Fatty Acids
  • Humans
  • Lipid Metabolism
  • Neoplasms* / therapy
  • T-Lymphocytes, Cytotoxic

Substances

  • Carnitine O-Palmitoyltransferase
  • Fatty Acids
  • CPT1A protein, human