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

• Published in: Cellular & molecular immunology 2021-07, Vol.18 (7), p.1761-1771
• Main Authors: Dumauthioz, Nina, Tschumi, Benjamin, Wenes, Mathias, Marti, Bastien, Wang, Haiping, Franco, Fabien, Li, Wenhui, Lopez-Mejia, Isabel C., Fajas, Lluis, Ho, Ping-Chih, Donda, Alena, Romero, Pedro, Zhang, Lianjun
• Format: Article
• Language: English
• Subjects: 631/250/1619/554/1834; 631/250/251; 631/67/580; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Cancer Vaccines; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Fitness; Immunological memory; Immunology; Lymphocytes; Lymphocytes T; Medical Microbiology; Melanoma; Memory cells; Metabolism; Mice; Microbiology; Mitochondria; Mitochondria - metabolism; Organelle Biogenesis; Oxidation; Oxidative phosphorylation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Phosphorylation; Tumor-infiltrating lymphocytes; Vaccination; Vaccine; Vaccines, Subunit
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/s41423-020-0365-3

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.