|
|
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.
 Previous Article | Next Article 
Submitted July 17, 2006
Accepted December 22, 2006
Inhibitory effect of tumor cell derived lactic acid on human T cells
Karin Fischer, Petra Hoffmann, Simon Voelkl, Norbert Meidenbauer, Julia Ammer, Matthias Edinger, Eva Gottfried, Sabine Schwarz, Gregor Rothe, Sabine Hoves, Kathrin Renner, Birgit Timischl, Andreas Mackensen, Leoni Kunz-Schughart, Reinhard Andreesen, Stefan W. Krause, and Marina Kreutz*
Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
Laboratory Center Bremen, Bremen, Germany
Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
Institute of Pathology, University of Regensburg, Regensburg, Germany
* Corresponding author; email: marina.kreutz{at}klinik.uni-regensburg.de.
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 (CTL) up to 95% and led to a 50% decrease in cytotoxic activity. A 24 h recovery period in lactic acid-free medium restored CTL function. CTLs infiltrating lactic acid-producing multicellular tumor spheroids showed a reduced cytokine production. Pre-treatment 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:
|
|
|
|
 
D. A. Tennant, R. V. Duran, H. Boulahbel, and E. Gottlieb
Metabolic transformation in cancer
Carcinogenesis,
August 1, 2009;
30(8):
1269 - 1280.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Mackensen
Adoptive Transfer of Tumor Antigen-specific CD8+ T-cells to Patients with Melanoma: Strategies to Improve Therapeutic Efficacy
ASCO Educational Book,
January 1, 2009;
2009(1):
521 - 524.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. McFate, A. Mohyeldin, H. Lu, J. Thakar, J. Henriques, N. D. Halim, H. Wu, M. J. Schell, T. M. Tsang, O. Teahan, et al.
Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells
J. Biol. Chem.,
August 15, 2008;
283(33):
22700 - 22708.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
