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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3812-3819. Prepublished online as a Blood First Edition Paper on January 25, 2007; DOI 10.1182/blood-2006-07-035972. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2006-07-035972v1 109/9/3812    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fischer, K. Articles by Kreutz, M. Search for Related Content PubMed PubMed Citation Articles by Fischer, K. Articles by Kreutz, M. Related Collections Immunobiology Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Inhibitory effect of tumor cell–derived lactic acid on human T cells Karin Fischer1, Petra Hoffmann1, Simon Voelkl1, Norbert Meidenbauer1, Julia Ammer1, Matthias Edinger1, Eva Gottfried1, Sabine Schwarz1, Gregor Rothe4, Sabine Hoves1, Kathrin Renner2, Birgit Timischl2, Andreas Mackensen1, Leoni Kunz-Schughart3, Reinhard Andreesen1, Stefan W. Krause1, and Marina Kreutz1 1 Department of Hematology and Oncology 2 Institute of Functional Genomics, and 3 Institute of Pathology, University of Regensburg, Regensburg, Germany; 4 Laboratory Center Bremen, Bremen, Germany A characteristic feature of tumors is high production of lactic acid due to enhanced glycolysis. Here, we show a positive correlation between lactate serum levels and tumor burden in cancer patients and examine the influence of lactic acid on immune functions in vitro. Lactic acid suppressed the proliferation and cytokine production of human cytotoxic T lymphocytes (CTLs) up to 95% and led to a 50% decrease in cytotoxic activity. A 24-hour recovery period in lactic acid–free medium restored CTL function. CTLs infiltrating lactic acid–producing multicellular tumor spheroids showed a reduced cytokine production. Pretreatment of tumor spheroids with an inhibitor of lactic acid production prevented this effect. Activated T cells themselves use glycolysis and rely on the efficient secretion of lactic acid, as its intracellular accumulation disturbs their metabolism. Export by monocarboxylate transporter-1 (MCT-1) depends on a gradient between cytoplasmic and extracellular lactic acid concentrations and consequently, blockade of MCT-1 resulted in impaired CTL function. We conclude that high lactic acid concentrations in the tumor environment block lactic acid export in T cells, thereby disturbing their metabolism and function. These findings suggest that targeting this metabolic pathway in tumors is a promising strategy to enhance tumor immunogenicity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Shime, M. Yabu, T. Akazawa, K. Kodama, M. Matsumoto, T. Seya, and N. Inoue Tumor-Secreted Lactic Acid Promotes IL-23/IL-17 Proinflammatory Pathway J. Immunol., June 1, 2008; 180(11): 7175 - 7183. [Abstract] [Full Text] [PDF]

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