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

• Published in: Trends in immunology Vol. 43; no. 12; pp. 969 - 977
• Main Authors: Apostolova, Petya, Pearce, Erika L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2022; Elsevier Limited
• Subjects: Acid production; Acidification; Acidity; Animals; Cancer; Carbon sources; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell culture; Culture media; Cytokines; Cytotoxicity; Gene expression; Glucose; Humans; Immune system; Immunosurveillance; Lactic acid; Lactic Acid - metabolism; Leukemia; Lymphatic system; Lymphocytes; Lymphocytes T; Mammals; Mass spectrometry; Mass spectroscopy; Melanoma; Metabolism; Metabolites; Metastasis; Neoplasms; Physiological effects; Physiology; Protons; T cell receptors; Tumor Microenvironment; Tumors
• ISSN: 1471-4906; 1471-4981
• DOI: 10.1016/j.it.2022.10.005

Many tumors and activated immune cells have high glycolytic activity and accumulate intracellular and potentially extracellular lactic acid. Besides acidifying the intratumoral pH, this might lead to an increased lactate concentration in the tumor microenvironment.An acidic pH and high lactate concentrations affect tumor and immune cell function. A low pH impairs the metabolic activity, proliferation, and cytokine production of human and mouse CD8+ T cells, while it can promote melanoma metastasis formation. Neutralizing intratumoral acidification might improve antitumor immunity and attenuate cancer metastasis.Novel findings from in vivo and in vitro isotope tracing establish lactate as a physiological carbon source fueling the tricarboxylic acid cycle in human and mouse cancer cells, mouse CD8+ T cells, regulatory T cells, and anti-inflammatory bone-marrow-derived macrophages.The intact function of lactate dehydrogenase in mouse CD8+ T cells is required for their antigen-specific expansion, cytokine production, and cytotoxicity in vivo.We posit that future efforts to improve the antitumor immune response should overcome the harmful effects of an acidic pH on CD8+ T cells while sustaining their physiological use of lactate as a metabolic fuel. Recent studies establish that the metabolic byproduct of glycolysis, lactate, is a physiological carbon source for both cancer and immune cells, including CD8+ T cells. Maintaining physiological lactate metabolism in antitumor CD8+ T cells is essential for their cytotoxic activity, while improving their resistance to acidic pH in the tumor microenvironment might be a beneficial candidate approach to cancer immunotherapy. 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.