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

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 asPrdm1andXbp1. While deletion ofLdhaprevented 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 TSCMcells, 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.

Modified Hypoxia Inducible Factor expression in CD8+ T cells increases anti-tumor efficacy

“…In total, 12155 individual transcripts were detected and mapped ( Figure 2B). Average transcript frequency and rank distribution was similar to previously published transcriptomic analyses of CD8+ T cells (25,26) including high levels of expression of genes defining CD8+ T-cell identity such as Gzmb, Cd8a, Cd3g, Prf1 and Ifng.…”

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

“…On the level of mRNA, we nd LDHA to be signi cantly downregulated upon 48 h of DCA treatment, further indicating decrease in fermentation. It is known that an acidic microenvironment is inhibiting the innate immune system in patients [114][115][116]. Interestingly, as lactate oxidation increases and lactic fermentation decreases as a consequence of DCA treatment, it represents indications of DCA is a de-toxifying stimulator of the microenvironment allowing both the innate immune system activation as well as the activation of the adaptive immune system.…”

“…Interestingly, as lactate oxidation increases and lactic fermentation decreases as a consequence of DCA treatment, it represents indications of DCA is a de-toxifying stimulator of the microenvironment allowing both the innate immune system activation as well as the activation of the adaptive immune system. Reducing lactate secretion through inhibition of LDHA has been shown to increase the effect of the immunotherapy including anti PD-L1 through increased activation of in ammatory and anti-tumors responses [114], and increase T-memory cell activation [115,116].…”

Lactate induced up‐regulation of KLHDC8A (Kelch domain‐containing 8A) contributes to the proliferation, migration and apoptosis of human glioma cells

“…Meanwhile, glioma cells stimulated with glucose displayed a significant increase in the accumulation of lactate which is the judgment of glycolytic metabolism ( Figure 7C). Furthermore, knockdown of LDHA, which catalyses the conversion of pyruvate to lactate in glycolysis, 30 resulted in the decrease of glucose-induced expression of KLHDC8A ( Figure 7D and Figure S4). These results suggest that lactate which produced by glycolysis is responsible for induction of KLHDC8A expression in the tumour microenvironment.…”