Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity

Cell Mol Immunol. 2021 Jul;18(7):1761-1771. doi: 10.1038/s41423-020-0365-3. Epub 2020 Feb 13.

Abstract

Memory CD8 T cells can provide long-term protection against tumors, which depends on their enhanced proliferative capacity, self-renewal and unique metabolic rewiring to sustain cellular fitness. Specifically, memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands. In contrast, tumor-infiltrating lymphocytes (TILs) display severe metabolic defects, which may underlie their functional decline. Here, we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1α expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1α maintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host. Altogether, our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation, metabolic fitness, and antitumor immunity in vivo.

Keywords: Anti-tumor immunity; CD8; Memory; Mitochondria; PGC-1α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines*
  • Mice
  • Mitochondria / metabolism
  • Organelle Biogenesis
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Vaccines, Subunit

Substances

  • Cancer Vaccines
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Vaccines, Subunit