Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation

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.

Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma

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Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343

“…Upon pathway activation, 4-1BB facilitates enhanced proliferation, cytokine production, and cytolytic activity of T and NK cells (5). Recent studies have pointed to the pathway's impact on mito-chondrial capacity and biogenesis of T cells to explain why 4-1BB agonism could help overcome the immunosuppressive landscape of the tumor microenvironment (6). While most research has focused on 4-1BB in the context of T effector cells, it should be noted that 4-1BB is also expressed on T-regulatory cells where its role remains contentious and requires further elucidation (7).…”

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency

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