title: LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.
abstract: 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 (Ldhalow) 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, Ldhalowand 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.
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Brand
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Singer
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Koehl
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Marlene
authors.initials: M
authors.lastname: Kolitzus
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schoenhammer
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Thiel
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Matos
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Bruss
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Klobuch
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Peter
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kastenberger
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schleicher
authors.affiliation: Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Andreas
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authors.lastname: Mackensen
authors.affiliation: Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany; Cellular Immunology, Pediatric Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine of the University Hospital Frankfurt, Goethe-University, 60590 Frankfurt, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ullrich
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fichtner-Feigl
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kesselring
authors.affiliation: Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany; Department of Internal Medicine II - Nephrology, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Matthias
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authors.lastname: Mack
authors.affiliation: Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Ritter
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schmid
authors.affiliation: Division of Immunology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam 1066CX, the Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Blank
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Katja
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authors.lastname: Dettmer
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
authors.forename: Stefan
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authors.lastname: Walenta
authors.affiliation: Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.affiliation: Institute of Research on Cancer and Aging, University of Nice-Sophia Antipolis, Centre A. Lacassagne, 06189 Nice, France; Centre Scientifique de Monaco (CSM), 98000 Monaco, Monaco.
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouyssegur
authors.affiliation: Medical University Innsbruck, Biocenter, Division of Developmental Immunology, 6020 Innsbruck, Austria; Tyrolean Cancer Research Institute, 6020 Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Martin Luther University Halle-Wittenberg, Institute of Medical Immunology Halle/Saale, 06112 Halle, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Steven
authors.affiliation: Martin Luther University Halle-Wittenberg, Institute of Medical Immunology Halle/Saale, 06112 Halle, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
authors.affiliation: Department of Dermatology, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schreml
authors.affiliation: Department of Dermatology, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Haferkamp
authors.affiliation: Department of Dermatology, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kohl
authors.affiliation: Department of Dermatology, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Sigrid
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authors.lastname: Karrer
authors.affiliation: Department of Dermatology, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Berneburg
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
authors.affiliation: Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueller-Klieser
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Renner
authors.affiliation: Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany. Electronic address: marina.kreutz@ukr.de.
authors.forename: Marina
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authors.lastname: Kreutz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007157:Immunologic Surveillance / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000096:biosynthesis* / Q000494:pharmacology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D010641:Phenotype; D019354:Sodium Lactate / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016207:Cytokines; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D019344:Lactic Acid; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D019354:Sodium Lactate