@article {13681, title = {Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity.}, journal = {Proc Natl Acad Sci U S A}, year = {2020}, month = {2020 Mar 02}, 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 (TSCM) 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 Prdm1 and Xbp1 While deletion of Ldha 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 TSCM 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.

}, issn = {1091-6490}, doi = {10.1073/pnas.1920413117}, author = {Hermans, Dalton and Gautam, Sanjivan and Garc{\'\i}a-Ca{\~n}averas, Juan C and Gromer, Daniel and Mitra, Suman and Spolski, Rosanne and Li, Peng and Christensen, Stephen and Nguyen, Rosa and Lin, Jian-Xin and Oh, Jangsuk and Du, Ning and Veenbergen, Sharon and Fioravanti, Jessica and Ebina-Shibuya, Risa and Bleck, Christopher and Neckers, Leonard M and Rabinowitz, Joshua D and Gattinoni, Luca and Leonard, Warren J} }