T lymphocytes expressing the T cell receptor (TCR)-γδ recognize unknown antigens on tumor cells. Here we identify metabolites of the mevalonate pathway as the tumor ligands that activate TCR-γδ cells. In tumor cells, blockade of hydroxy-methylglutaryl-CoA reductase (HMGR), the rate limiting enzyme of the mevalonate pathway, prevents both accumulation of mevalonate metabolites and recognition by TCR-γδ cells. When metabolite accumulation is induced by overexpressing HMGR or by treatment with nitrogen-containing bisphosphonate drugs, tumor cells derived from many tissues acquire the capacity to stimulate the same TCR-γδ population. Accumulation of mevalonate metabolites in tumor cells is a powerful danger signal that activates the immune response and may represent a novel target of tumor immunotherapy.
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20 January 2003
Article|
January 13 2003
Human T Cell Receptor γδ Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells
Hans-Jürgen Gober,
Hans-Jürgen Gober
1Experimental Immunology, Department of Research, University Hospital, Basel
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Magdalena Kistowska,
Magdalena Kistowska
1Experimental Immunology, Department of Research, University Hospital, Basel
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Lena Angman,
Lena Angman
1Experimental Immunology, Department of Research, University Hospital, Basel
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Paul Jenö,
Paul Jenö
2Department of Biochemistry, Biozentrum, University of Basel, CH-4056 Basel, Switzerland
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Lucia Mori,
Lucia Mori
1Experimental Immunology, Department of Research, University Hospital, Basel
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Gennaro De Libero
Gennaro De Libero
1Experimental Immunology, Department of Research, University Hospital, Basel
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Hans-Jürgen Gober
1Experimental Immunology, Department of Research, University Hospital, Basel
Magdalena Kistowska
1Experimental Immunology, Department of Research, University Hospital, Basel
Lena Angman
1Experimental Immunology, Department of Research, University Hospital, Basel
Paul Jenö
2Department of Biochemistry, Biozentrum, University of Basel, CH-4056 Basel, Switzerland
Lucia Mori
1Experimental Immunology, Department of Research, University Hospital, Basel
Gennaro De Libero
1Experimental Immunology, Department of Research, University Hospital, Basel
Address correspondence to Gennaro De Libero, Experimental Immunology, Department of Research, University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland. Phone: 41-61-265-2327; Fax: 41-61-265-2350; E-mail: [email protected]
The online version of this paper contains supplemental material.
*
Abbreviations used in this paper: FPP, farnesylpyrophosphate; IPP, isopentenylpyrophosphate; PAM, pamidronate; ZOL, zoledronate.
Received:
August 23 2002
Revision Received:
December 02 2002
Accepted:
December 03 2002
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 197 (2): 163–168.
Article history
Received:
August 23 2002
Revision Received:
December 02 2002
Accepted:
December 03 2002
Citation
Hans-Jürgen Gober, Magdalena Kistowska, Lena Angman, Paul Jenö, Lucia Mori, Gennaro De Libero; Human T Cell Receptor γδ Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells . J Exp Med 20 January 2003; 197 (2): 163–168. doi: https://doi.org/10.1084/jem.20021500
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