Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation
Alvaro Teijeira, Sara Labiano, Saray Garasa, Iñaki Etxeberria, Eva Santamaría, Ana Rouzaut, Michel Enamorado, Arantza Azpilikueta, Susana Inoges, Elixabet Bolaños, Maria Angela Aznar, Alfonso R Sánchez-Paulete, David Sancho, Ignacio Melero
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.
CITATION Cancer Immunol Res. 2018 Jul;6(7):798-811. doi: 10.1158/2326-6066.CIR-17-0767. Epub 2018 Apr 20.