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

Alvaro Teijeira,Elixabet Bolaños,Maria Angela Aznar,Michel Enamorado,Iñaki Etxeberria,Sara Labiano,Ignacio Melero,Arantza Azpilikueta,Susana Inoges,Alfonso R Sánchez-Paulete,Ana Rouzaut,David Sancho,Saray Garasa,Eva Santamaría

doi:10.1158/2326-6066.cir-17-0767

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.

Highlights

Mitochondria critically regulate metabolism and apoptosis in T cells, prompting the growing interest in how modulation of mitochondrial metabolism and dynamics can control T-cell function, survival, and memory differentiation [1, 2]
Human and mouse T-cell cultures under CD137 costimulation acquire a more blastic morphology and more rapidly acidify the culture medium than their non-costimulated counterparts. Because these changes are indicative of more glycolysis, we explored whether agonistic anti-CD137 costimulation could increase mitochondrial function
We studied whether mitochondrial changes were induced by the physiological ligand, CD137L [31]

Summary

Introduction

Mitochondria critically regulate metabolism and apoptosis in T cells, prompting the growing interest in how modulation of mitochondrial metabolism and dynamics can control T-cell function, survival, and memory differentiation [1, 2]. This is the case of T cells within the tumor microenvironment, where the limiting concentration of some metabolites that are consumed by tumor cells influences T-cell metabolism and function [1, 3]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

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