Improving anti-tumor T cell immunity by targeting LDH-A functions beyond the Warburg effect

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Divergence in the metabolic reprogramming is critical to effectively imprint distinct T cell fates. To meet their bioenergetic demands, T effector (TEFF) cells use aerobic glycolysis leading to lactate production (the Warburg effect), whereas T memory cells (TM) switch to fatty acid oxidation (FAO). It remains poorly understood how transition of TEFF to TM cells correlates with simultaneous metabolic reprogramming. It is also unclear whether glycolysis itself regulates such transition events. The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the conversion of pyruvate to lactate in the last step of glycolysis, a hallmark of the Warburg effect. LDH-A is upregulated in human cancers and is associated with aggressive tumor outcomes. Conversely, inactivation of LDH-A in tumor cells results in decreased tumorigenesis and regression of established tumors. We generated LDH-Aflox/floxCD4-Cre (LDH-A-/-) and LDH-Aflox/flox (LDH-Acon) mice, in which LDH-A is deleted only in T cells, to study how targeting the hallmark step of the Warburg effect would affect T cell function. Antigen-specific CD8+ LDH-A-/- TEFF rapidly expanded, differentiated to TCM and TSCM and displayed potent response on antigen mediated re-challenge. Moreover, tumor-infiltrating CD8+ LDH-A-/- T cells retained robust mitochondrial function in the tumor microenvironment and inhibited tumor growth. Metabolite tracer studies revealed that LDH-A-/- CD8+ T cells had enhanced glucose flux, elevated intermediates of glycolysis, TCA cycle, and glucose-derived acetyl-coA but diminished usage of glutamine for TCA anaplerosis. This altered metabolic preference has been identified in embryonic stem cells (ES) cells, where it promotes histone/DNA demethylation by aKG-dependent demethylases and maintains stemness. Moreover, similarly to ES cells, LDH-A-/- CD8+ T cells had increased histone acetylation mediated via glycolysis-derived acetyl-CoA. These metabolism-driven epigenetic changes might be responsible for the rapid differentiation of LDH-A-/- cells to TCM and TSCM, which have stemness features. Our findings support the novel hypothesis that glycolysis has a key role on memory T cell differentiation by generating pyruvate and that it is the pyruvate-acetyl-CoA step not the pyruvate-lactate step, which contributes to the generation of cellular identity and has a mechanistic role on the transcriptional and epigenetic state of T cells. Understanding and recapitulating this metabolic state might provide a novel method to generate potent antigen-specific TEFF and TM cells for cancer immunotherapy. To investigate this, we will pursue the following specific aim to determine: 1. How LDH-A mediated metabolic changes affect the differentiation program of tumor-specific T cells. 2. How LDH-A targeting impacts the epigenetic regulation of TM cell differentiation. 3. How LDH-A targeting affects the properties and function of tumor-specific T cells.