Abstract 639: Morphological changes in mitochondria induced by CD137 (4-1BB) co-stimulation on CD8 T cells

Abstract

Abstract Metabolism has emerged as a fundamental biological process in the control of immunological functions of T cells, playing essential roles in survival and differentiation of these immune cells. Mitochondria are key organelles in controlling these processes by performing fundamental steps in aerobic respiration, fatty acid metabolism and in the control of apoptosis. Recently, Carl June and colleagues showed that CARs engineered with the cytoplasmic tail of 4-1BB were able to promote oxidative phosphorylation in T cells as a result of enhanced mitochondrial biogenesis. CD137 (4-1BB) is an immunostimulatory receptor of the TNFR family expressed on the surface of antigen-activated T cells. Treatment with agonist monoclonal antibodies targeting 4-1BB is showing promising results for immunotherapy of cancer. In this work, we observed that stimulation of 4-1BB with agonistic mAbs was able to raise the mitochondrial membrane potential on human CD8 T cells. 4-1BB co-stimulated CD8 T cells showed enlarged mitochondria (up to 3μm diameter) with a round shape when observed by confocal or transmission electron microscopy. We observed that CD8 T cells from DLNs (drainig lymph nodes) of tumors in mice treated with agonistic anti-4-1BB antibodies also contained enlarged mitochondria. By double fluorescence labeling of mitochondria prior and after activation, we could ascertain that enlarged mitochondria were a product of preexisting mitochondria rather than de novo generated organelles. This observation prompted us to study the regulation of mitochondrial dynamics by 4-1BB receptor. 4-1BB stimulation induced an increase in expression of the mitochondrial fusion protein OPA-1. By Super-resolution microscopy with AiryScan detectors we observed more pronounced co-localization of OPA-1 with mitochondrial membrane in 4-1BB co-stimulated T cells than in T cells activated only by CD3 crosslinking. Our results indicate an important role of 4-1BB in the regulation of mitochondrial morphology and performance in such a way that can be relevant for various T cell functions. Citation Format: Sara Labiano, Álvaro Teijeira, Arantza Azpilikueta, Ángela Aznar, Elixabet Bolaños, Ignacio Melero. Morphological changes in mitochondria induced by CD137 (4-1BB) co-stimulation on CD8 T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 639. doi:10.1158/1538-7445.AM2017-639