Abstract
Although cancer immunotherapy is effective against hematological malignancies, it is less effective against solid tumors due in part to significant metabolic challenges present in the tumor microenvironment (TME), where infiltrated CD8+ T cells face fierce competition with cancer cells for limited nutrients. Strong metabolic suppression in the TME is often associated with impaired T cell recruitment to the tumor site and hyporesponsive effector function via T cell exhaustion. Increasing evidence suggests that mitochondria play a key role in CD8+ T cell activation, effector function, and persistence in tumors. In this study, we showed that there was an increase in overall mitochondrial function, including mitochondrial mass and membrane potential, during both mouse and human CD8+ T cell activation. CD8+ T cell mitochondrial membrane potential was closely correlated with granzyme B and IFN-γ production, demonstrating the significance of mitochondria in effector T cell function. Additionally, activated CD8+ T cells that migrate on ICAM-1 and CXCL12 consumed significantly more oxygen than stationary CD8+ T cells. Inhibition of mitochondrial respiration decreased the velocity of CD8+ T cell migration, indicating the importance of mitochondrial metabolism in CD8+ T cell migration. Remote optical stimulation of CD8+ T cells that express our newly developed “OptoMito-On” successfully enhanced mitochondrial ATP production and improved overall CD8+ T cell migration and effector function. Our study provides new insight into the effect of the mitochondrial membrane potential on CD8+ T cell effector function and demonstrates the development of a novel optogenetic technique to remotely control T cell metabolism and effector function at the target tumor site with outstanding specificity and temporospatial resolution.
Highlights
Despite recent advances in the treatment of malignant tumors, cancer continues to be a widespread disease and a leading cause of death
During the activation of T cells, there was an increase in mitochondrial mass and mitochondrial membrane potential from Day 0 through Day 5, and both mitochondrial signals plateaued after Day 5 (Figures 1A, B)
Similar to what was seen in human T cells, mouse CD8+ T cells exhibit an increase in mitochondrial mass and mitochondrial membrane potential from Day 0 through Day 4, though a decrease or plateau was observed on Day 7 (Figures 1C, D), suggesting that increases in mitochondrial mass and function coincide with CD8+ T cell proliferation and activation
Summary
Despite recent advances in the treatment of malignant tumors, cancer continues to be a widespread disease and a leading cause of death. Chimeric antigen receptor-transduced T cells (CAR-T cells) have been designed to augment CD8+ T cell antitumor activity and are extremely successful in treating hematological malignancies [2, 3]. This approach is ineffective against solid tumors due in part to the immunosuppressive tumor microenvironment (TME) which promotes T cell exhaustion [4,5,6]. Reprogramming effector CD8+ T cell metabolism to increase mitochondrial mass and function has been shown to improve antitumor activity [5]. We further characterized a novel tool, a photoactivatable proton pump called “OptoMito-On,” to increase mitochondrial ATP production in CD8+ T cells with the aim of improving T cell immunotherapies for solid malignancies
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