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

TitleLactate dehydrogenase inhibition synergizes with IL-21 to promote CD8 T cell stemness and antitumor immunity.
Publication TypeJournal Article
Year of Publication2020
AuthorsHermans, D, Gautam, S, García-Cañaveras, JC, Gromer, D, Mitra, S, Spolski, R, Li, P, Christensen, S, Nguyen, R, Lin, J-X, Oh, J, Du, N, Veenbergen, S, Fioravanti, J, Ebina-Shibuya, R, Bleck, C, Neckers, LM, Rabinowitz, JD, Gattinoni, L, Leonard, WJ
JournalProc Natl Acad Sci U S A
Volume117
Issue11
Pagination6047-6055
Date Published2020 03 17
ISSN1091-6490
KeywordsAnimals, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Line, Tumor, Enzyme Inhibitors, Humans, Immunologic Memory, Immunotherapy, Adoptive, Interleukin-2, Interleukins, L-Lactate Dehydrogenase, Melanoma, Experimental, Mice, Primary Cell Culture, Stem Cells
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>

DOI10.1073/pnas.1920413117
Alternate JournalProc Natl Acad Sci U S A
PubMed ID32123114
PubMed Central IDPMC7084161
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States