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Reduced Expression of the Mevalonate Pathway Enzyme Farnesyl Pyrophosphate Synthase Unveils Recognition of Tumor Cells by V9V2 T Cells¹

Jianqiang Li^*, Marco J. Herold^2,*, Brigitte Kimmel, Ingrid Müller^*, Bladimiro Rincon-Orozco^3,*, Volker Kunzmann^4, and Thomas Herrmann^4,5,*

^* Institut für Virologie und Immunbiologie and Medizinische Klinik und Poliklinik II, Julius-Maximilians Universität Würzburg, Würzburg, Germany

Human V9V2 T cells are characterized by a unique specificity for certain tumors (e.g., Daudi), cells presenting so-called phosphoantigens such as isopentenyl pyrophosphate (IPP), or cells treated with aminobisphosphonates. We now report conversion of hematopoietic and nonhematopoietic tumor cell lines into V9V2 T cell activators by means of short hairpin RNA-mediated knockdown of expression of the IPP-consuming enzyme, farnesyl pyrophosphate synthase (FPPS). FPPS knockdown cells activated V9V2 T cells, as measured by increased levels of CD69 and CD107a, killing of FPPS knockdown cells, and induction of IFN- secretion. The IPP-synthesis-inhibiting drug mevastatin reduced V9V2 T cell activation by FPPS knockdown cells but not activation by the phosphoantigen bromohydrin pyrophosphate. In conclusion, our data support the concept of V9V2 T cells as sensors of a dysregulated isoprenoid metabolism and suggest therapeutic down-modulation of FPPS expression as an additional tool to target tumor cells to V9V2 T cell-mediated immunosurveillance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Interdiziplinäres Zentrum für Klinische Forschung Grant No. 01KS9603.

² Current address: Walter and Eliza Hall Institute of Medical Research Melbourne, 1G Royal Parade, Parkville, 3050 Victoria, Australia.

³ Current address: Deutsches Krebsforschungszentrum, Division of Viral Transformation Mechanisms, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany.

⁴ V.K. and T.H. shared senior authorship.

⁵ Address correspondence and reprint requests to Dr. Thomas Herrmann, Institut für Virologie und Immunbiologie, Versbacherstrasse 7, D-97078 Würzburg, Germany. E-mail address: herrmann-t{at}vim.uni-wuerzburg.de

⁶ Abbreviations used in this paper: HMB-PP, (E)-4-hydroxy-3-methyl-but-enyl pyrophosphate; BrHPP, bromohydrin pyrophosphate; EYFP, enhanced yellow fluorescent protein; FPPS, farnesyl pyrophosphate synthase; GGPS, geranylgeranyl pyrophosphate synthase; HMG, 3-hydroxy-3-methyl-glutaryl; IPP, isopentenyl pyrophosphate; shRNA, short hairpin RNA.