Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism

CD8+ T cells are critical mediators of antitumor immunity but differentiate into a state of dysfunction, known as exhaustion, after experiencing persistent TCR stimulation and metabolic stress in the tumor microenvironment (TME). Exhausted T cells are characterized by the sustained upregulation of co-inhibitory molecules and reduced stemness and polyfunctionality. The TME also creates an immunosuppressive metabolic environment via reduced levels of vital nutrients and oxygen combined with increased catabolic waste products. Additionally, highly glycolytic tumor and stromal cells secrete lactic acid, acidifying the extracellular space. How exhausted T cells survive and function in the face of this altered metabolite balance remains unknown. Here we show terminally exhausted T cells in the TME upregulate a newly characterized, monocarboxylate transporter 11 (MCT11, encoded by Slc16a11), enabling uptake of monocarboxylates like lactic acid, which enforces their state of dysfunction. MCT11 expression requires both the core exhaustion program induced through chronic activation and metabolic stress signals, like hypoxia, originating within tissues. Overexpression of MCT11 in tumor-specific T cells accelerated exhaustion: increasing co-inhibitory marker expression and decreasing polyfunctionality. Conditional deletion of MCT11 in T cells reduced Texh cell lactic acid uptake and resulted in improved effector functions and improved response to immunotherapy. Further, a monoclonal antibody targeting MCT11 could block lactate uptake specifically in Texh cells, which, when used therapeutically in tumor-bearing mice, resulted in significantly reduced tumor growth, inducing complete regressions and immunologic memory. Our data support a model in which the exhaustion program upregulates MCT11, rendering Texh cells sensitive to toxic lactic acid present at high levels in the tumor microenvironment. MCT11 represents an attractive target to edit in therapeutic T cells or block using antibodies to render exhausted T cells impervious to lactic acid, allowing for tumor eradication. Overall design: MCT11-KO (Slc16a11fl/fl x CD4Cre) mice (3 each) were inoculated with B16 melanoma tumors. At day +14, infiltrating CD8+ exhausted T cells were sorted (PD-1hiTim3+ fraction) from tumors and subjected to bulk RNA sequencing. For analysis, publicly available RNA-seq data from wild-type C57BL/6 CD8+ exhausted T cells isolated from B16 tumors in a similar fashion were used as controls (Ford et al., Sci Immunol 2022, PMID 35930654, GSE175408): samples GSM5333036, GSM5333037, and GSM5333038.