Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation
2018; American Association for Cancer Research; Volume: 6; Issue: 7 Linguagem: Inglês
10.1158/2326-6066.cir-17-0767
ISSN2326-6074
AutoresÁlvaro Teijeira, Sara Labiano, Saray Garasa, Iñaki Etxeberría, Eva Santamaría, Ana Rouzaut, Michel Enamorado, Arantza Azpilikueta, Susana Inogès, Elixabet Bolaños, M. Ángela Aznar, Alfonso R. Sánchez-Paulete, David Sancho, Ignacio Melero,
Tópico(s)Immune Cell Function and Interaction
ResumoT 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.
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