Cholesterol Induces CD8 + T Cell Exhaustion in the Tumor Microenvironment

Cell Metab. 2019 Jul 2;30(1):143-156.e5. doi: 10.1016/j.cmet.2019.04.002. Epub 2019 Apr 25.

Abstract

Tumor-infiltrating T cells often lose their effector function; however, the mechanisms are incompletely understood. We report that cholesterol in the tumor microenvironment induces CD8+ T cell expression of immune checkpoints and exhaustion. Tumor tissues enriched with cholesterol and cholesterol content in tumor-infiltrating CD8+ T cells were positively and progressively associated with upregulated T cell expression of PD-1, 2B4, TIM-3, and LAG-3. Adoptively transferred CD8+ T cells acquired cholesterol, expressed high levels of immune checkpoints, and became exhausted upon entering a tumor. Tumor culture supernatant or cholesterol induced immune checkpoint expression by increasing endoplasmic reticulum (ER) stress in CD8+ T cells. Consequently, the ER stress sensor XBP1 was activated and regulated PD-1 and 2B4 transcription. Inhibiting XBP1 or reducing cholesterol in CD8+ T cells effectively restored antitumor activity. This study reveals a mechanism underlying T cell exhaustion and suggests a new strategy for restoring T cell function by reducing cholesterol to enhance T cell-based immunotherapy.

Keywords: CD8+ T cells; cholesterol; exhaustion; immune checkpoints; tumor microenvironment.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cholesterol / blood*
  • Flow Cytometry
  • Humans
  • Immunoprecipitation
  • Immunotherapy
  • Melanoma, Experimental / blood
  • Mice
  • Programmed Cell Death 1 Receptor / metabolism
  • Real-Time Polymerase Chain Reaction
  • Tumor Microenvironment / physiology*

Substances

  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Cholesterol