Teijeira, AlvaroLabiano, SaraGarasa, SarayEtxeberria, IñakiSantamaría, EvaRouzaut, AnaEnamorado, MichelAzpilikueta, ArantzaInoges, SusanaBolaños, ElixabetAznar, Maria AngelaSánchez-Paulete, Alfonso RSancho, DavidMelero, Ignacio2022-10-252022-10-252018-07Cancer Immunol Res . 2018 Jul;6(7):798-811http://hdl.handle.net/20.500.12105/15097T 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.engVoRhttp://creativecommons.org/licenses/by/4.0/4-1BB LigandAnimalsBiomarkersCD8-Positive T-LymphocytesCytokinesCytotoxicity, ImmunologicFemaleGene SilencingHumansLymphocytes, Tumor-InfiltratingMelanoma, ExperimentalMembrane Potential, MitochondrialMiceMice, KnockoutMitochondriaNeoplasmsRNA, Small InterferingT-LymphocytesTumor MicroenvironmentAtribución 4.0 Internacional2967887467798-81110.1158/2326-6066.CIR-17-07672326-6074Cancer immunology researchopen access