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Cell Metab. 2016 Nov 8;24(5):657-671. doi: 10.1016/j.cmet.2016.08.011. Epub 2016 Sep 15.

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

Author information

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.

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, Ldhalow 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.

PMID:
27641098
DOI:
10.1016/j.cmet.2016.08.011
[Indexed for MEDLINE]
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