Figure S1 shows that CD8 T cells with high mitochondrial transmembrane potential after CD137 stimulation have enlarged mitochondria. Fig S2 shows that CD137 induced mitochondrial changes are not due to enrichment of specific CD8 T cells subsets. Figure S3 shows that mitochondrial enhanced functions induced by CD137 activation are not a consequence of autocrine secretion of cytokines. Fig S4 shows that spare respiratory capacity induced by CD137 activation is dependent on fatty acid oxidation. Figure S5 explores regulation of mitochondrial biogenesis and fusion related genes upon CD137 activation. Fig S6 shows functional effects of OPA knockdown in CD8 T cells. Figure S7 shows the implication of Akt pathway on enhanced mitochondrial function by CD137 activation. Figure S8 shows that CD137KO CD8 T cells have intrinsic mitochondrial defects upon CD28 activation. Figure S9 shows that CD137 activation enhances mitochondrial parameters in tumor infiltrating lymphocytes. Fig S10 shows engrafment abilities and memory markers of OTI cells in B16OVA tumor bearing mice upon OPA silencing and CD137 mAb treatment.
ARTICLE ABSTRACT
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.
