HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Conrad, H. Articles by Bernhard, H. Search for Related Content PubMed PubMed Citation Articles by Conrad, H. Articles by Bernhard, H.

CTLs Directed against HER2 Specifically Cross-React with HER3 and HER4¹

Heinke Conrad^*,, Kerstin Gebhard^*,, Holger Krönig^*, Julia Neudorfer^*, Dirk H. Busch^,, Christian Peschel^* and Helga Bernhard^2,*,

^* Department of Hematology/Oncology and Department of Microbiology, Immunology and Hygiene, Technical University of Munich, Klinikum Rechts der Isar, Munich, Germany; and Clinical Cooperation Group "Antigen-Specific Immunotherapy," Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, and Technical University Munich, Munich, Germany

The human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated Ag by T cell-based immunotherapeutical strategies such as cancer vaccines and adoptive T cell transfer. The prerequisite for a successful T cell-based therapy is the induction of T cells capable of recognizing the HER2-expressing tumor cells. In this study, we generated human cytotoxic T cell clones directed against the HER2_369–377 epitope known to be naturally presented with HLA-A*0201. Those HER2-reactive CTLs, which were also tumor lytic, exhibited a similar lysis pattern dividing the targets in lysable and nonlysable tumor cells. Several HER2-expressing tumor cells became susceptible to CTL-mediated lysis after IFN- treatment and, in parallel, up-regulated molecules of the Ag-presenting machinery, indicating that the tumor itself also contributes to the success of CTL-mediated killing. Some of the HER2_369–377-reactive T cells specifically cross-reacted with the corresponding peptides derived from the family members HER3 and/or HER4 due to a high sequence homology. The epitopes HER3_356–364 and HER4_361–369 were endogenously processed and contributed to the susceptibility of cell lysis by HER cross-reacting CTLs. The principle of "double" or "triple targeting" the HER Ags by cross-reacting T cells will impact the further development of T cell-based therapies.

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 the Research Council of Germany Grant SFB 456 (to H.B. and D.H.B.) and the Wilhelm Sander foundation Grant 2000.017.3 (to H.B.).

² Address correspondence and reprint requests to Dr. Helga Bernhard, Third Medical Department, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, D-81675 Munich, Germany. E-mail address: helga.bernhard{at}lrz.tum.de

³ Abbreviations used in this paper: HER, human epidermal growth factor receptor; APM, Ag-processing machinery; DC, dendritic cell; ECD, extracellular domain; LMP, low m.w. protein; MFI, mean fluorescence intensity; MFI, difference in MFI; siRNA, small interfering RNA; siHER2, siRNA against HER2; siHER3, siRNA against HER3; siCo, control siRNA; LCL, lymphoblastoid cell line.