Journal
CANCER IMMUNOLOGY RESEARCH
Volume 6, Issue 7, Pages 798-811Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-17-0767
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Funding
- imCORE Network (Roche Genentech)
- MINECO [SAF2014-52361-R, 2017-83267-C2-1-R]
- European Commission
- Fundacion de la Asociacion Espanola Contra el Cancer (AECC)
- Fundacion BBVA
- Juan de la Cierva contract, MINECO
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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 F 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 rumor-reactive CD8(+) T cells from cancer-hearing mice were invigorated by agonist mAb to CD137, whereas mitochondria) 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-CD 137 WAS critically dependent on OPA-1 expression in transferred CD8(+) T cells. Moreover, stimulation of CD137 with CD137 mAb in shortterm 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 CD 117 costimulation of T cells. (C)2018 AACR.
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