Abstract B016: Lactate uptake through MCT11 enforces dysfunction in terminally exhausted T cells

Abstract 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 (Texh) 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 Texh cells survive and function in the face of this altered metabolite balance remains unclear. Recent studies have shown that lactate can be incorporated into the TCA cycle by CD8+ T cells and that it can be utilized in the TME as a fuel source by regulatory T cells and macrophages. We hypothesized that CD8+ tumor-infiltrating lymphocytes (TIL) may take also take up lactate as to meet their metabolic demands in the TME. Here, we show via RNAseq and flow cytometry staining that Texh cells upregulate a newly characterized monocarboxylate transporter, MCT11 (encoded by Slc16a11), enabling uptake of lactic acid which can drive their dysfunction in the TME. 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 decreased their polyfunctionality, while conditional deletion of MCT11 in T cells reduced lactic acid uptake in Texh cells and improved effector function and response to immunotherapy. Further, a monoclonal antibody targeting MCT11 reduced 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 in lactate-rich tumors. Our data support a model in which the exhaustion program upregulates MCT11, rendering exhausted T 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. Citation Format: Ronal M. Peralta, Greg M. Delgoffe. Lactate uptake through MCT11 enforces dysfunction in terminally exhausted T cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B016.