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oai:repisalud.isciii.es:20.500.12105/150972024-09-27T08:04:48Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Teijeira, Alvaro author Labiano, Sara author Garasa, Saray author Etxeberria, Iñaki author Santamaría, Eva author Rouzaut, Ana author Enamorado, Michel author Azpilikueta, Arantza author Inoges, Susana author Bolaños, Elixabet author Aznar, Maria Angela author Sánchez-Paulete, Alfonso R author Sancho, David author Melero, Ignacio author 2018-07 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. Cancer Immunol Res . 2018 Jul;6(7):798-811 10.1158/2326-6066.CIR-17-0767 2326-6074 Cancer immunology research 29678874 http://hdl.handle.net/20.500.12105/15097 Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation.