Enhancing CD8 + T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

Cancer Cell. 2017 Sep 11;32(3):377-391.e9. doi: 10.1016/j.ccell.2017.08.004.

Abstract

How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8+ TILs enhance peroxisome proliferator-activated receptor (PPAR)-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8+ TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8+ TILs' antigen specificity. Further promoting FA catabolism improves the CD8+ TILs' ability to slow tumor progression. PD-1 blockade delays tumor growth without changing TIL metabolism or functions. It synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and even complete cures.

Keywords: CD8(+) T cells; HIF-1α; TILs; co-inhibitors; fatty acid catabolism; fenofibrate; hypoglycemia; hypoxia; melanoma; tumor microenvironment.

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

  • Animals
  • Antigens, CD / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / ultrastructure
  • Cell Hypoxia
  • Disease Progression
  • Fatty Acids / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Glucose / pharmacology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunotherapy*
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Melanoma / immunology*
  • Melanoma / pathology
  • Melanoma / therapy*
  • Melanoma / ultrastructure
  • Mice, Inbred C57BL
  • Oxygen / pharmacology
  • Programmed Cell Death 1 Receptor / metabolism
  • Stress, Physiological
  • Treatment Outcome
  • Tumor Microenvironment / immunology*

Substances

  • Antigens, CD
  • CD223 antigen
  • Fatty Acids
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Glucose
  • Oxygen