Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8⁺ T cell stemness and antitumor immunity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 11; pp. 6047 - 6055
• Main Authors: Hermans, Dalton, Gautam, Sanjivan, García-Cañaveras, Juan C., Gromer, Daniel, Mitra, Suman, Spolski, Rosanne, Li, Peng, Christensen, Stephen, Nguyen, Rosa, Lin, Jian-Xin, Oh, Jangsuk, Du, Ning, Veenbergen, Sharon, Fioravanti, Jessica, Ebina-Shibuya, Risa, Bleck, Christopher, Neckers, Leonard M., Rabinowitz, Joshua D., Gattinoni, Luca, Leonard, Warren J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.03.2020
• Subjects: Adoptive transfer; Anticancer properties; Antitumor activity; Biological Sciences; CD8 antigen; Cell differentiation; Clonal deletion; Cytokines; Dehydrogenase; Dehydrogenases; Differentiation (biology); Effector cells; Exhaustion; Gene expression; Glycolysis; Immunity; Immunological memory; Immunotherapy; Inhibition; Interleukin 2; Interleukin 21; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Lymphocytes; Lymphocytes T; Memory cells; Metabolism; Nuclear receptors; Oxidative phosphorylation; PD-1 protein; Phosphorylation; Pyruvic acid; Receptors; Stem cells; Tricarboxylic acid cycle; Tumors; LDH; IL-2; immunometabolism; IL-21; adoptive immunotherapy

Interleukin (IL)-2 and IL-21 dichotomously shape CD8⁺ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. Here we investigated the role of metabolic pr...