Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment

Abstract

Lactic acid production has been regarded as a mechanism by which malignant cells escape immunosurveillance. Recent technological advances in mass spectrometry and the use of cell culture media with a physiological nutrient composition have shed new light on the role of lactic acid and its conjugate lactate in the tumor microenvironment. Here, we review novel work identifying lactate as a physiological carbon source for mammalian tumors and immune cells. We highlight evidence that its use as a substrate is distinct from the immunosuppressive acidification of the extracellular milieu by lactic acid protons. Together, data suggest that neutralizing the effects of intratumoral acidity while maintaining physiological lactate metabolism in cytotoxic CD8⁺ T cells should be pursued to boost anti-tumor immunity.

Figure 1.. Lactic acid and lactate metabolism

In mammalian cells, glycolysis converts glucose to two molecules of pyruvate with a net yield of two molecules of adenosine triphosphate (ATP) and two molecules of reduced nicotinamide adenine nucleotide (NADH). Pyruvate can be imported into the mitochondria and converted to acetyl-coenzyme A (acetyl-CoA), which enters the tricarboxylic acid (TCA) cycle. Alternatively, the enzyme lactate dehydrogenase (LDH) can convert pyruvate to lactate. This reaction is bidirectional, so when lactate is high, LDH converts it to pyruvate that can either enter the TCA cycle or initiate the process of gluconeogenesis, i.e., de novo glucose synthesis [2]. Lactate can be exported via the monocarboxylate transporters MCT1–4, which also function bidirectionally [13]. Acquisition of a proton, for instance, from NADH, leads to the conversion of lactate to its conjugate, lactic acid. In aqueous solution with physiological pH, lactic acid dissociates almost entirely to lactate and hydrogen ions (H⁺), thus acidifying the extracellular microenvironment. Lactate can also be used to produce lactyl-coenzyme A (lactyl-CoA) and affect gene transcription via histone lactylation [43]. Figure adapted from “Lactic acid fermentation” by Biorender.com (2022). Retrieved from https://app.biorender.com/biorender-templates, last accessed on October 8, 2022. Abbreviations: Acetyl-CoA: acetyl-coenzyme A, ADP: adenosine diphosphate, ATP: adenosine triphosphate, H⁺: hydrogen ion, Lactyl-CoA: lactyl-coenzyme A, LDH: lactate dehydrogenase, MCT: monocarboxylate transporter, NAD/NADH: oxidized/reduced nicotinamide adenine nucleotide, TCA: tricarboxylic acid.

Key figure, Figure 2.. Effects of lactic acid and lactate on mammalian cell metabolism and function

(A) Tumor cells with high aerobic glycolysis generate lactate via lactate dehydrogenase (LDH) [3], [21]. In mouse breast cancer and multiple myeloma cell lines, lactate can be exported via the monocarboxylate transporter 1 or 4 (MCT1, 4) simultaneously with protons and acidify the extracellular space in vitro [50], [51]. Lung and pancreatic cancer cells in mice and humans in vivo acquire lactate via MCT1, which is then converted to pyruvate to fuel the tricarboxylic acid (TCA) [24], [25]. (B) Lactic acid can enter the cytosol of cytotoxic CD8⁺ T lymphocytes and decrease the intracellular pH. Acidification leads to the inhibition of glycolysis, proliferation, and cytokine production in mice and humans [18], [21], [23]. Lactate can also be taken up via MCT1 and fuel the TCA cycle in mouse CD8⁺ T cells in vitro [30]. At higher concentrations (40 mM), lactate acts as a histone deacetylase (HDAC) inhibitor in vitro, which enables the increased transcription of Tcf7 and drives a stem cell-like phenotype in mice [36]. (C) For intratumoral regulatory CD4⁺ T cells, lactate uptake via MCT1 is an essential fuel for the TCA cycle [38]. Furthermore, it can be used for gluconeogenesis and reduces the requirement for extracellular glucose. Lactate and lactic acid exposure are tightly linked to T_reg proliferation and suppressive function in mice and humans [38], [39], [40]. (D) Extracellular lactic acid regulates the transcription of genes such as Vegf, Arg1, and Retnla in mouse macrophages, influencing their anti-inflammatory differentiation [19], [42], [43]. Figure created with Biorender.com. Abbreviations: Acetyl-CoA: acetyl-coenzyme A, ATP: adenosine triphosphate, H⁺: hydrogen ion, HDAC: histone deacetylase, MCT: monocarboxylate transporter, OXPHOS: oxidative phosphorylation, PEP: phosphoenolpyruvate, TCA: tricarboxylic acid, Treg: regulatory T cells.