LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells
Open accessAbstract
Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha low ) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2 -/- γc -/- mice, lacking lymphocytes and NK cells, and in Ifng -/- mice, Ldha low and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.
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Cancer cells compete with immune cells for glucose uptake (by SLC2A1/GLUT1), produce lactic acid (by LDHA), and generate an acidic extracellular milieu (through the activity of CA9), all of which are immunosuppressive.
“Cancer cells compete with immune cells for glucose uptake (by SLC2A1/GLUT1), produce lactic acid (by LDHA), and generate an acidic extracellular milieu (through the activity of CA9), all of which are immunosuppressive (77–86).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [77]
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References 38 · Cited by 2,039
- Authors
- Brand, A., Singer, K., Koehl, G. E., Kolitzus, M., Schoenhammer, G., Thiel, A., Matos, C., Bruss, C., Klobuch, S., Peter, K., Kastenberger, M., Bogdan, C., Schleicher, U., Mackensen, A., Ullrich, E., Fichtner-Feigl, S., Kesselring, R., Mack, M., Ritter, U., Schmid, M., Blank, C., Dettmer, K., Oefner, P. J., Hoffmann, P., Walenta, S., Geissler, E. K., Pouyssegur, J., Villunger, A., Steven, A., Seliger, B., Schreml, S., Haferkamp, S., Kohl, E., Karrer, S., Berneburg, M., Herr, W., Mueller-Klieser, W., Renner, K., & Kreutz, M.
- Affiliations
- University Hospital Regensburg (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Goethe University Frankfurt (DE)
- University of Regensburg (DE)
- The Netherlands Cancer Institute (NL)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Innsbruck Medical University (AT)
- Martin Luther University Halle-Wittenberg (DE)
- Corresponding author
- Kreutz, Marina
- ORCID
- Brand, Almut
- Singer, Katrin
- Matos, Carina
- Klobuch, Sebastian
- Peter, Katrin
- Bogdan, Christian
- Schleicher, Ulrike
- Ullrich, Evelyn
- Kesselring, Rebecca
- Mack, Matthias
- Ritter, Uwe
- Schmid, Maximilian
- Blank, Christian
- Dettmer, Katja
- Oefner, Peter J.
- Hoffmann, Petra
- Geissler, Edward K.
- Villunger, Andreas
- Steven, André
- Seliger, Barbara
- Schreml, Stephan
- Haferkamp, Sebastian
- Karrer, Sigrid
- Berneburg, Mark
- Herr, Wolfgang
- Renner, Kathrin
- Kreutz, Marina
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 24
- Issue
- 5
- Pages
- 657-671
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2519020116
- Cited by
- 2,039
- References
- 38
- Citations by year
- 2026: 324 · 2025: 319 · 2024: 265 · 2023: 248 · 2022: 245 · 2021: 211 · 2020: 149 · 2019: 112 · 2018: 95 · 2017: 62 · 2016: 8
- FWCI
- 38.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- LDHA, lactate accumulation, melanoma, tumor surveillance, T cells, natural killer cells, interferon-gamma, NFAT, tumor immune evasion, T cell activation, tumor microenvironment
- MeSH terms
- Lactate Dehydrogenase 5, Animals, Cell Count, Cell Survival, Glycolysis, Humans, Immunologic Surveillance, Interferon-gamma, Isoenzymes, Killer Cells, Natural, L-Lactate Dehydrogenase, Male, Melanoma, Mice, Inbred C57BL, Phenotype, T-Lymphocytes, Up-Regulation, Cytokines, Apoptosis, CD8-Positive T-Lymphocytes, Lactic Acid, Sodium Lactate, Cell Line, Tumor, Cell Proliferation, NFATC Transcription Factors
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