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A Cryptic Vascular Endothelial Growth Factor T-Cell Epitope: Identification and Characterization by Mass Spectrometry and T-Cell Assays

Andreas O. Weinzierl¹, Dominik Maurer¹, Florian Altenberend¹, Nicole Schneiderhan-Marra⁵, Karin Klingel³, Oliver Schoor¹, Dorothee Wernet², Thomas Joos⁵, Hans-Georg Rammensee¹ and Stefan Stevanovi^1,4

¹ Department of Immunology, Institute for Cell Biology and ² Institute of Clinical and Experimental Transfusion Medicine, University of Tübingen; ³ Department of Molecular Pathology, University Hospital Tübingen; ⁴ Proteome Centrum Tübingen, Tübingen, Germany and ⁵ NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany

Requests for reprints: Stefan Stevanovi, Department of Immunology, Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany. Phone: 49-7071-29-87645; Fax: 49-7071-29-5653; E-mail: stefan.stevanovic{at}uni-tuebingen.de.

Key Words: VEGF • T-cell epitope • differential mass spectrometry • cancer • renal cell carcinoma

Vascular endothelial growth factor (VEGF) is involved in various physiologic processes, such as angiogenesis or wound healing, but is also crucial in pathologic events, such as tumor growth. Thus, clinical anti-VEGF treatments have been developed that could already show beneficial effects for cancer patients. In this article, we describe the first VEGF-derived CD8⁺ T-cell epitope. The natural HLA ligand SRFGGAVVR was identified by differential mass spectrometry in two primary renal cell carcinomas (RCC) and was significantly overpresented on both tumor tissues. SRFGGAVVR is derived from a cryptic translated region of VEGF presumably by initiation of translation at the nonclassic start codon CUG⁴⁹⁹. SRFGGAVVR-specific T cells were generated in vitro using peptide-loaded dendritic cells or artificial antigen-presenting cells. SRFGGAVVR-specific CD8⁺ T cells, identified by HLA tetramer analysis after in vitro stimulation, were fully functional T effector cells, which were able to secrete IFN- on stimulation and killed tumor cells in vitro. Additionally, we have quantitatively analyzed VEGF mRNA and protein levels in RCC tumor and normal tissue samples by gene chip analysis, quantitative reverse transcription-PCR, in situ hybridization, and bead-based immunoassay. In the future, T cells directed against VEGF as a tumor-associated antigen may represent a possible way of combining peptide-based anti-VEGF immunotherapy with already existent anti-VEGF cancer therapies. [Cancer Res 2008;68(7):2447–54]

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