Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity
Autor: | Haiping Wang, Isabel C. Lopez-Mejia, Mathias Wenes, Bastien Marti, Nina Dumauthioz, Pedro Romero, Wenhui Li, Benjamin O. Tschumi, Alena Donda, Lluis Fajas, Ping-Chih Ho, Fabien Franco, Lianjun Zhang |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Immunology PGC-1α Oxidative phosphorylation CD8-Positive T-Lymphocytes Biology Mitochondrion Cancer Vaccines Article Mice 03 medical and health sciences 0302 clinical medicine Memory Coactivator Animals Immunology and Allergy Cytotoxic T cell CD8-positive T cells Receptor Beta oxidation Organelle Biogenesis CD8 Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Mitochondria Cell biology CD8-Positive T-Lymphocytes/metabolism Mitochondria/metabolism Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism Vaccines Subunit Anti-tumor immunity 030104 developmental biology Infectious Diseases Mitochondrial biogenesis 030220 oncology & carcinogenesis Tumour immunology Immunotherapy |
Zdroj: | Cellular and Molecular Immunology Cellular & molecular immunology, vol. 18, no. 7, pp. 1761-1771 |
ISSN: | 2042-0226 1672-7681 |
DOI: | 10.1038/s41423-020-0365-3 |
Popis: | 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. |
Databáze: | OpenAIRE |
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