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

Abstract

CD8⁺ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (T_ex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally T_ex cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by T_ex cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in T_ex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which T_ex cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME.