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T and NK lymphocytes express CD137 (4-1BB), a costimulatory receptor of the TNFR family whose function is exploitable for cancer immunotherapy. Mitochondria regulate the function and survival of T lymphocytes. Herein, we show that CD137 costimulation provided by agonist mAb and CD137L (4-1BBL) induced mitochondria enlargement that resulted in enhanced mitochondrial mass and transmembrane potential in human and mouse CD8+ T cells. Such mitochondrial changes increased T-cell respiratory capacities and were critically dependent on mitochondrial fusion protein OPA-1 expression. Mass and function of mitochondria in tumor-reactive CD8+ T cells from cancer-bearing mice were invigorated by agonist mAb to CD137, whereas mitochondrial baseline mass and function were depressed in CD137-deficient tumor reactive T cells. Tumor rejection induced by the synergistic combination of adoptive T-cell therapy and agonistic anti-CD137 was critically dependent on OPA-1 expression in transferred CD8+ T cells. Moreover, stimulation of CD137 with CD137 mAb in short-term cultures of human tumor-infiltrating lymphocytes led to mitochondria enlargement and increased transmembrane potential. Collectively, these data point to a critical link between mitochondrial morphology and function and enhanced antitumor effector activity upon CD137 costimulation of T cells. Cancer Immunol Res; 6(7); 798-811. ©2018 AACR.

Original publication




Journal article


Cancer immunology research

Publication Date





798 - 811


Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.


T-Lymphocytes, CD8-Positive T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Mitochondria, Animals, Mice, Knockout, Humans, Mice, Neoplasms, Melanoma, Experimental, RNA, Small Interfering, Cytokines, Cytotoxicity, Immunologic, Gene Silencing, Female, 4-1BB Ligand, Membrane Potential, Mitochondrial, Tumor Microenvironment, Biomarkers