| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
βTCRs Selected by Vaccination with Natural versus Altered Self-Antigen in Melanoma Patients1
*Division of Experimental Oncology, Multidisciplinary Oncology Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland;
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne University Hospital (CHUV), Lausanne, Switzerland; and
Department of Research CHUV, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
Immunotherapy of cancer is often performed with altered "analog" peptide Ags optimized for HLA class I binding, resulting in enhanced immunogenicity, but the induced T cell responses require further evaluation. Recently, we demonstrated fine specificity differences and enhanced recognition of naturally presented Ag by T cells after vaccination with natural Melan-A/MART-1 peptide, as compared with analog peptide. In this study, we compared the TCR primary structures of 1489 HLA-A*0201/Melan-A26–35-specific CD8 T cells derived from both cohorts of patients. Although a strong preference for TRAV12-2 segment usage was present in nearly all patients, usage of particular TRAJ gene segments and CDR3
composition differed slightly after vaccination with natural vs analog peptide. Moreover, TCR β-chain repertoires were broader after natural than analog peptide vaccination. In all patients, we observed a marked conservation of the CDR3β amino acid composition with recurrent sequences centered on a glycyl-leucyl/valyl/alanyl-glycyl motif. In contrast to viral-specific TCR repertoires, such "public" motifs were primarily expressed by nondominant T cell clonotypes, which contrasted with "private" CDR3β signatures frequently found in T cell clonotypes that dominated repertoires of individual patients. Interestingly, no differences in functional avidity were observed between public and private T cell clonotypes. Collectively, our data indicate that T cell repertoires generated against natural or analog Melan-A peptide exhibited slightly distinct but otherwise overlapping and structurally conserved TCR features, suggesting that the differences in binding affinity/avidity of TCRs toward pMHC observed in the two cohorts of patients are caused by subtle structural TCR variations.
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 study was sponsored and supported by the Swiss National Center of Competence in Research (NCCR) Molecular Oncology, the Ludwig Institute for Cancer Research, NY, and the Swiss National Science Foundation Grant 3200B0-118123/1, the Oncosuisse Grant OCS-01995-02–2007, and the Wilhelm Sander-Foundation (Germany). P.R. was supported in part by a grant from the EU FP6, "Cancer Immunotherapy."
2 D.E.S. and N.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Nathalie Rufer, CHUV/University of Lausanne, Hôpital Orthopédique, niv 5, Aile Est, Avenue Pierre-Decker 4, CH-1011 Lausanne, Switzerland. E-mail address: Nathalie.Rufer{at}unil.ch
4 Abbreviations used in this paper: IFA, Incomplete Freund’s Adjuvant; EM, effector-memory.
5 The online version of this article contains supplementary material.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
