Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8 T cell stemness and antitumor immunity. Author Dalton Hermans, Sanjivan Gautam, Juan García-Cañaveras, Daniel Gromer, Suman Mitra, Rosanne Spolski, Peng Li, Stephen Christensen, Rosa Nguyen, Jian-Xin Lin, Jangsuk Oh, Ning Du, Sharon Veenbergen, Jessica Fioravanti, Risa Ebina-Shibuya, Christopher Bleck, Leonard Neckers, Joshua Rabinowitz, Luca Gattinoni, Warren Leonard Publication Year 2020 Type Journal Article Abstract 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 (T) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as and While deletion of prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21-induced metabolism but caused major transcriptomic changes, including the suppression of IL-21-induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of T cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21. Keywords Animals, Mice, Humans, Cell Line, Tumor, Cell Differentiation, Stem Cells, Enzyme Inhibitors, Primary Cell Culture, L-Lactate Dehydrogenase, CD8-Positive T-Lymphocytes, Immunologic Memory, Immunotherapy, Adoptive, Interleukin-2, Interleukins, Melanoma, Experimental Journal Proc Natl Acad Sci U S A Volume 117 Issue 11 Pages 6047-6055 Date Published 2020 Mar 17 ISSN Number 1091-6490 DOI 10.1073/pnas.1920413117 Alternate Journal Proc Natl Acad Sci U S A PMCID PMC7084161 PMID 32123114 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML