@article{3773,
  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},
  author = {Dalton Hermans and Sanjivan Gautam and Juan Garc{\'\i}a-Ca{\~n}averas and Daniel Gromer and Suman Mitra and Rosanne Spolski and Peng Li and Stephen Christensen and Rosa Nguyen and Jian-Xin Lin and Jangsuk Oh and Ning Du and Sharon Veenbergen and Jessica Fioravanti and Risa Ebina-Shibuya and Christopher Bleck and Leonard Neckers and Joshua Rabinowitz and Luca Gattinoni and Warren Leonard},
  title = {Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8 T cell stemness and antitumor immunity.},
  abstract = { <p>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.</p> },
  year = {2020},
  journal = {Proc Natl Acad Sci U S A},
  volume = {117},
  pages = {6047-6055},
  month = {2020 Mar 17},
  issn = {1091-6490},
  doi = {10.1073/pnas.1920413117},
  language = {eng},
}