Dumauthioz et al. showed that adoptively transferred OT-1 CD8+ T cells transduced to overexpress PGC-1α – a key regulator of mitochondrial biogenesis – had enhanced metabolic fitness (indicated by increased mitochondrial activity); had improved persistence in mice with Listeria Ova infection, in mice vaccinated with OVA, and in B16-OVA-bearing mice; favored a central memory over a tissue-resident memory phenotype; and had an enhanced recall response upon rechallenge. In tumor-bearing mice, these T cells accumulated in the tumor site and reduced tumor growth – an effect that was further improved in combination with PD-1 blockade.
Contributed by Anna Scherer
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-1alpha), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1alpha-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1alpha expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1alpha 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.
Author Info: (1) Translational Tumor Immunology Group, Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland. Department of Fundamental Oncology, University of Lausanne, Epalin
Author Info: (1) Translational Tumor Immunology Group, Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland. Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. (2) Translational Tumor Immunology Group, Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland. Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. (3) Translational Tumor Immunology Group, Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland. Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. (4) Translational Tumor Immunology Group, Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland. Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. (5) Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. Ludwig Cancer Research Institute Lausanne Branch, Epalinges, Switzerland. (6) Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. Ludwig Cancer Research Institute Lausanne Branch, Epalinges, Switzerland. (7) Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China. Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, 215123, China. (8) Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. (9) Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. (10) Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. Ludwig Cancer Research Institute Lausanne Branch, Epalinges, Switzerland. (11) Translational Tumor Immunology Group, Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland. Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. (12) Translational Tumor Immunology Group, Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland. Pedro.Romero@unil.ch. Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. Pedro.Romero@unil.ch. (13) Translational Tumor Immunology Group, Ludwig Cancer Research, University of Lausanne, Epalinges, Switzerland. zlj@ism.cams.cn. Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland. zlj@ism.cams.cn. Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 100005, Beijing, China. zlj@ism.cams.cn. Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, 215123, China. zlj@ism.cams.cn.
