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      LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

      1 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 3 , 1 , 4 , 4 , 5 , 6 , 7 , 2 , 8 , 9 , 10 , 11 , 12 , 12 , 3 , 13 , 2 , 14 , 15 , 16 , 16 , 17 , 17 , 17 , 17 , 17 , 1 , 13 , 3 , 18

      Cell metabolism

      Elsevier BV

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          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 (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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          Author and article information

          Journal
          Cell Metab.
          Cell metabolism
          Elsevier BV
          1932-7420
          1550-4131
          Nov 08 2016
          : 24
          : 5
          Affiliations
          [1 ] Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
          [2 ] Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
          [3 ] Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany.
          [4 ] Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
          [5 ] Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
          [6 ] 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.
          [7 ] Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany.
          [8 ] Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany; Department of Internal Medicine II - Nephrology, University Hospital Regensburg, 93053 Regensburg, Germany.
          [9 ] Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
          [10 ] Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
          [11 ] Division of Immunology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam 1066CX, the Netherlands.
          [12 ] Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
          [13 ] Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
          [14 ] 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.
          [15 ] Medical University Innsbruck, Biocenter, Division of Developmental Immunology, 6020 Innsbruck, Austria; Tyrolean Cancer Research Institute, 6020 Innsbruck, Austria.
          [16 ] Martin Luther University Halle-Wittenberg, Institute of Medical Immunology Halle/Saale, 06112 Halle, Germany.
          [17 ] Department of Dermatology, University Hospital Regensburg, 93053 Regensburg, Germany.
          [18 ] 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.
          Article
          S1550-4131(16)30427-2
          10.1016/j.cmet.2016.08.011
          27641098
          237f646d-7f5b-4874-bd80-3deae70ff217

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