Liu and Wang et al. found the glucose transporter GLUT10 to be rapidly upregulated and trafficked to the cell surface during CD8+ T cell activation, and increased GLUT10 abundance on tumor-infiltrating CD8+ effector T cells. GLUT10 deletion in T cells inhibited the activation and proliferation, and reduced the antitumor efficacy of CD8+ T cells in vivo. Tumor cell-derived lactic acid bound directly to GLUT10, interfering with CD8+ T cell glucose uptake and effector functions. PG10.3, a peptide derived from GLUT10, overcame lactate inhibition. PG10.3 combined with a GLUT1 inhibitor or anti-PD-1 further enhanced antitumor efficacy in patient-derived tumor xenograft models.
Contributed by Ute Burkhardt
ABSTRACT: CD8(+) T cell activation leads to the rapid proliferation and differentiation of effector T cells (T(effs)), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8(+) T(effs), the mechanisms that regulate CD8(+) T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8(+) T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8(+) T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8(+) T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8(+) T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8(+) T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti-programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8(+) T cells and identify that TME accumulated lactic acid inhibits CD8(+) T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8(+) T cell-mediated antitumor effects.
Author Info: (1) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese
Author Info: (1) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (2) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (3) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. (4) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. (5) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. (6) State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China. (7) Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200120, China. (8) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (9) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (10) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (11) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (12) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (13) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (14) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (15) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (16) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (17) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (18) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. (19) Marine College, Shandong University, Weihai 264200, China. (20) Marine College, Shandong University, Weihai 264200, China. (21) State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
