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Unexpected Abundance of HLA Class II Presented Peptides in Primary Renal Cell Carcinomas

Jörn Dengjel^1,2, Maria-Dorothea Nastke², Cécile Gouttefangeas², Gitsios Gitsioudis², Oliver Schoor², Florian Altenberend², Margret Müller², Björn Krämer², Anna Missiou², Martina Sauter³, Jörg Hennenlotter⁴, Dorothee Wernet⁵, Arnulf Stenzl⁴, Hans-Georg Rammensee², Karin Klingel³ and Stefan Stevanovi^2,6

Authors' Affiliations: ¹ Immatics Biotechnologies GmbH; ² Department of Immunology, Institute for Cell Biology; Departments of ³ Molecular Pathology, ⁴ Urology, and ⁵ Transfusion Medicine; and ⁶ Proteom Centrum, University of Tübingen, Tübingen, Germany

Requests for reprints: Stefan Stevanovi, Department of Immunology, Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany. Phone: 49-7071-2987645; Fax: 49-7071-295653; E-mail: stefan.stevanovic{at}uni-tuebingen.de.

Purpose: To elicit a long-lasting antitumor immune response, CD8⁺ and CD4⁺ T cells should be activated. We attempted to isolate HLA-DR–presented peptides directly from dissected solid tumors, in particular from renal cell carcinoma, to identify MHC class II ligands from tumor-associated antigens (TAA) for their use in peptide-based immunotherapy.

Experimental Design: Tumor specimens were analyzed by immunohistochemical staining for their HLA class II expression. HLA class II peptides were subsequently isolated and identified by mass spectrometry. Gene expression analysis was done to detect genes overexpressed in tumor tissue. Peptides from identified TAAs were used to induce peptide-specific CD4⁺ T-cell responses in healthy donors and in tumor patients.

Results: In the absence of inflammation, expression of MHC class II molecules is mainly restricted to cells of the immune system. To our surprise, we were able to isolate and characterize hundreds of class II peptides directly from primary dissected solid tumors, especially from renal cell carcinomas, and from colorectal carcinomas and transitional cell carcinomas. Infiltrating leukocytes expressed MHC class II molecules and tumor cells, very likely under the influence of IFN. Our list of identified peptides contains ligands from several TAAs, including insulin-like growth factor binding protein 3 and matrix metalloproteinase 7. The latter bound promiscuously to HLA-DR molecules and were able to elicit CD4⁺ T-cell responses.

Conclusions: Thus, our direct approach will rapidly expand the limited number of T-helper epitopes from TAAs for their use in clinical vaccination protocols.

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