Peralta et al. investigated the impact of lactic acid buildup and hypoxia in the TME on the functionality of exhausted CD8+ T cells (Tex). Chronic TCR stimulation uniquely upregulated Slc16a11, the gene encoding the monocarboxylate transporter 11 (MCT11), on Tex, but not progenitor Tex, resulting in increased uptake and metabolism of lactic acid and decreased functionality. Hypoxia further upregulated MCT11 expression via Hif1a. Conditional deletion of MCT11 in T cells improved effector function, while targeting MCT11 with a blocking mAb reduced tumor growth in murine syngeneic and human xenograft models, and synergized with anti-PD-1.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (2) Department of Immun
Author Info: (1) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (2) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (3) Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (4) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (5) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (6) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (7) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA. (8) Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (9) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (10) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (11) Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (12) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (13) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (14) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA. (15) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (16) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (17) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. gdelgoffe@pitt.edu. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. gdelgoffe@pitt.edu.
