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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lustgarten, J. Articles by Pinilla, C. Search for Related Content PubMed PubMed Citation Articles by Lustgarten, J. Articles by Pinilla, C.

Identification of Cross-Reactive Peptides Using Combinatorial Libraries Circumvents Tolerance against Her-2/neu-Immunodominant Epitope¹

Joseph Lustgarten^2,*, Ana L. Dominguez^* and Clemencia Pinilla^2,

^* Sidney Kimmel Cancer Center and Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

The majority of the currently defined tumor-associated Ags are often overexpressed products of normal cellular genes. Therefore, tolerance deletes high-affinity T cells directed against the TAAs, leaving only a low-affinity repertoire. We have demonstrated previously that the T cell repertoire against the immunodominant p773–782 A2.1-Her-2/neu-restricted peptide has low affinity in A2xneu mice (Her-2/neu mice crossed with A2.1/Kb mice), compared with A2xFVB mice (A2.1/Kb crossed with FVB-wild-type mice). Immunizations with this peptide have a minor impact in preventing tumor growth in A2xneu mice. Therefore, attempts to expand these responses may be of little clinical value. We hypothesized that if not all possible cross-reactive peptides (CPs) are naturally processed and presented, the possibility exists that T cells against these CPs persist in the repertoire and can be used to induce antitumor responses with higher avidity against native epitopes present on the tumor cells. We have used the positional scanning synthetic peptide combinatorial library methodology to screen the p773–782 T cell clone. The screening data identified potential amino acids that can be substituted in the primary sequences of the p773–782 peptide. The designed CPs induce CTL responses of higher affinity in A2xneu mice compared with the native p773–783 peptide. These CTLs recognize A2⁺-Her-2/neu⁺ tumors with high efficiency. Moreover, multiple immunizations with CPs significantly prolonged the survival of tumor-bearing A2xneu mice. These results have demonstrated that it was possible to circumvent tolerance with the identification of CPs and that these peptides could be of significant clinical value.

This article has been cited by other articles:

				S. Sharma, A. L. Dominguez, S. Z. Manrique, F. Cavallo, S. Sakaguchi, and J. Lustgarten Systemic Targeting of CpG-ODN to the Tumor Microenvironment with Anti-neu-CpG Hybrid Molecule and T Regulatory Cell Depletion Induces Memory Responses in BALB-neuT Tolerant Mice Cancer Res., September 15, 2008; 68(18): 7530 - 7540. [Abstract] [Full Text] [PDF]

				A. L. Dominguez and J. Lustgarten Implications of Aging and Self-Tolerance on the Generation of Immune and Antitumor Immune Responses Cancer Res., July 1, 2008; 68(13): 5423 - 5431. [Abstract] [Full Text] [PDF]

				H. Conrad, K. Gebhard, H. Kronig, J. Neudorfer, D. H. Busch, C. Peschel, and H. Bernhard CTLs Directed against HER2 Specifically Cross-React with HER3 and HER4 J. Immunol., June 15, 2008; 180(12): 8135 - 8145. [Abstract] [Full Text] [PDF]