Hypoxia Induces Mitochondrial Defect That Promotes T Cell Exhaustion in Tumor Microenvironment Through MYC-Regulated Pathways.

T cell exhaustion is an obstacle to immunotherapy for solid tumors. An understanding of the mechanism by which T cells develop this phenotype in solid tumors is needed. Here, hypoxia, a feature of the tumor microenvironment, causes T cell exhaustion (T-Exh) by inducing a mitochondrial defect. Upon exposure to hypoxia, activated T cells with a T(Exh)phenotype are characterized by mitochondrial fragmentation, decreased ATP production, and decreased mitochondrial oxidative phosphorylation activity. The T(Exh)phenotype is correlated with the downregulation of the mitochondrial fusion protein mitofusin 1 (MFN1) and upregulation of miR-24. Overexpression of miR-24 alters the transcription of many metabolism-related genes including its target genesMYCand fibroblast growth factor 11 (FGF11). Downregulation ofMYCandFGF11induces T(Exh)differentiation, reduced ATP production and a loss of the mitochondrial mass in T cell receptor (TCR)-stimulated T cells. In addition, we determined that MYC regulates the transcription ofFGF11andMFN1. In nasopharyngeal carcinoma (NPC) tissues, the T cells exhibit an increased frequency of exhaustion and loss of mitochondrial mass. In addition, inhibition of miR-24 signaling decreases NPC xenograft growth in nude mice. Our findings reveal a mechanism for T cell exhaustion in the tumor environment and provide potential strategies that target mitochondrial metabolism for cancer immunotherapy.