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Cross-Reactive CD4⁺ T Cells against One Immunodominant Tumor-Derived Epitope in Melanoma Patients¹

Pavol Kudela^*, Bratislav Janjic^*, Julien Fourcade^*, Florence Castelli, Pedro Andrade^*, John M. Kirkwood^*, Talal El-Hefnawy, Massimo Amicosante^¶, Bernard Maillere and Hassane M. Zarour^2,*,

^* Department of Medicine and Division of Hematology/Oncology, Department of Immunology, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Commissariat a l’energic atomique-iBiTecs, Service d’Ingenierie Moleculaire des Proteines, Gif-sur-Yvette, France; and ^¶ Department of Internal Medicine, University of Rome "Tor Vergata," Rome, Italy

TCRs exhibit a high degree of specificity but may also recognize multiple and distinct peptide-MHC complexes, illustrating the so-called cross-reactivity of TCR-peptide-MHC recognition. In this study, we report the first evidence of CD4⁺ T cells recognizing the same tumor peptide-epitope from NY-ESO-1, in the context of multiple HLA-DR and HLA-DP molecules. These cross-reactive CD4⁺ T cells recognized not only autologous but also allogenic dendritic cells previously loaded with the relevant protein (i.e., the normally processed and presented epitope). Using clonotypic real-time RT-PCR, we have detected low frequencies of CD4⁺ T cells expressing one cross-reactive TCR from circulating CD4⁺ T cells of patients with stage IV melanoma either spontaneously or after immunization but not in normal donors. The maintenance of cross-reactive tumor Ag-specific CD4⁺ T cells in PBLs of cancer patients required the presence of tumor Ag/epitope in the context of the MHC molecule used to prime the Ag-specific CD4⁺ T cells. Our findings have significant implications for the optimization of TCR gene transfer immunotherapies widely applicable to cancer patients.

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 National Institutes of Health/National Cancer Institute Grants CA90360 and CA112198 (to H.M.Z) and a Clinical Trial Grant/Melanoma Initiative from the Cancer Research Institute (to H.M.Z).

² Address correspondence and reprint requests to Dr. Hassane M. Zarour, Hillman Cancer Center, Research Pavilion, Suite 1.32a, 5117 Centre Avenue, Pittsburgh, PA 15213-2582. E-mail address: zarourhm{at}upmc.edu

³ Abbreviations used in this paper: pMHC, peptide-MHC; DC, dendritic cell; β-Gus, β-glucuronidase.

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