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      Lactate dehydrogenase: a marker of diminished antitumor immunity

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          ABSTRACT

          Lactate dehydrogenase (LDH) levels are inversely related with response to checkpoint inhibitors. Elevated LDH levels are the product of enhanced glycolytic activity of the tumor and tumor necrosis due to hypoxia, the latter being associated with high tumor burden. In this review, we elucidate the effects of glycolysis and hypoxia on antitumor immunity and set forth ways to improve response to immunotherapy in cancer patients with elevated LDH levels. We discuss the current knowledge on combining immunotherapy with glycolysis inhibitors, anti-acidifying drugs, anti-angiogenic or cytoreductive therapy.

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

          Almut Brand, Katrin Singer, Gudrun Koehl … (2016)
          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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            Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells.

            Andrea Facciabene, Xiaohui Peng, Ian S Hagemann … (2011)
            Although immune mechanisms can suppress tumour growth, tumours establish potent, overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (T(reg)) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth. ©2011 Macmillan Publishers Limited. All rights reserved
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              The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes.

              Arnold J. Levine, Anna M. Puzio-Kuter (2010)
              Cells from some tumors use an altered metabolic pattern compared with that of normal differentiated adult cells in the body. Tumor cells take up much more glucose and mainly process it through aerobic glycolysis, producing large quantities of secreted lactate with a lower use of oxidative phosphorylation that would generate more adenosine triphosphate (ATP), water, and carbon dioxide. This is the Warburg effect, which provides substrates for cell growth and division and free energy (ATP) from enhanced glucose use. This metabolic switch places the emphasis on producing intermediates for cell growth and division, and it is regulated by both oncogenes and tumor suppressor genes in a number of key cancer-producing pathways. Blocking these metabolic pathways or restoring these altered pathways could lead to a new approach in cancer treatments.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncoimmunology
                Journal ID (iso-abbrev): Oncoimmunology
                Journal ID (publisher-id): KONI
                Journal ID (publisher-id): koni20
                Title: Oncoimmunology
                Publisher: Taylor & Francis
                ISSN (Print): 2162-4011
                ISSN (Electronic): 2162-402X
                Publication date Collection: 2020
                Publication date (Electronic): 26 February 2020
                Publication date PMC-release: 26 February 2020
                Volume: 9
                Issue: 1
                Electronic Location Identifier: 1731942
                Affiliations
                [a ]Department of Medical Oncology, The Radboud University Medical Center , Nijmegen, The Netherlands
                [b ]Department of Medical Oncology, Rijnstate Hospital , Arnhem, The Netherlands
                [c ]Department of Medical Oncology, Isala Oncology Center , Zwolle, The Netherlands
                [d ]Department of Medical Oncology, The Netherlands Cancer Institute , Amsterdam, The Netherlands
                [e ]Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, Netherlands
                Author notes
                CONTACT Sandra van Wilpe Sandra.vanWilpe@ 123456radboudumc.nl Department of Medical Oncology, The Radboud University Medical Center , Geert Grooteplein Zuid 10, Nijmegen 6525, The Netherlands
                Article
                Publisher ID: 1731942
                DOI: 10.1080/2162402X.2020.1731942
                PMC ID: 7051189
                PubMed ID: 32158624
                SO-VID: 0d266388-d127-4c15-bccc-c82ba6ad7efb
                Copyright © © 2020 Radboudumc. Published with license by Taylor & Francis Group, LLC.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 15 October 2019
                Date revision received : 9 January 2020
                Date accepted : 12 January 2020
                Page count
                Figures: 2, Tables: 1, References: 96, Pages: 12
                Categories
                Subject: Review

                ScienceOpen disciplines: Immunology
                Keywords: cancer,checkpoint inhibitors,immune system,lactate dehydrogenase
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: cancer, checkpoint inhibitors, immune system, lactate dehydrogenase

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