Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells.
T lymphocytes expressing the T cell receptor (TCR)-gammadelta recognize unknown antigens on tumor cells. Here we identify metabolites of the mevalonate pathway as the tumor ligands that activate TCR-gammadelta 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-gammadelta 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-gammadelta 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.
Gober
Hans-Jürgen
HJ
Experimental Immunology, Department of Research, University Hospital, University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
Kistowska
Magdalena
M
Angman
Lena
L
Jenö
Paul
P
Mori
Lucia
L
De Libero
Gennaro
G
D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D007167:Immunotherapy; D008213:Lymphocyte Activation; D008798:Mevalonic Acid / Q000276:immunology* / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D010766:Phosphorylation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D016692:Receptors, Antigen, T-Cell, gamma-delta; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid