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Human T Cell Receptor Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells

¹ Experimental Immunology, Department of Research, University Hospital, Basel
² Department of Biochemistry, Biozentrum, University of Basel, CH-4056 Basel, Switzerland

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: Gennaro.DeLibero{at}unibas.ch

T lymphocytes expressing the T cell receptor (TCR)- recognize unknown antigens on tumor cells. Here we identify metabolites of the mevalonate pathway as the tumor ligands that activate TCR- 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- 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- 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.

Key Words: antigen recognition • tumor antigen • HMGR • IPP • bisphosphonate drugs

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