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Comprehensive Analysis of HLA-DR- and HLA-DP4-Restricted CD4⁺ T Cell Response Specific for the Tumor-Shared Antigen Survivin in Healthy Donors and Cancer Patients¹

Xiao-Fei Wang^*, Jerome Kerzerho^*, Olivier Adotevi, Hélène Nuyttens^*, Cecile Badoual, Gaetan Munier^*, Stéphane Oudard, Shuiping Tu, Eric Tartour and Bernard Maillère^2,*

^* Commissariat à l'Energie Atomique, Institut de Biologie et Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéine, Gif Sur Yvette; EA 4054 Université Paris-Descartes-Ecole Nationale Vétérinaire d'Alfort, Hôpital Européen Georges Pompidou, Unité d'Immunologie Biologique et Unité d'Anatomie Pathologique Assistance Publique-Hôpitaux de Paris, Paris; Service d'Oncologie Médicale, Hôpital Européen Georges Pompidou, EA 4054 Université Paris-Descartes, Paris, France; and Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

Because of the wide distribution of the survivin Ag in a variety of tumors, we have investigated the survivin-specific CD4⁺ T cell response in healthy donors and cancer patients. Screening of the entire sequence of survivin for HLA class II binding led to the identification of seven HLA-DR promiscuous peptides, including four HLA-DP4 peptides. All of the peptides were able to prime in vitro CD4⁺ T cells of eight different healthy donors. The peptide-specific T cell lines were stimulated by dendritic cells loaded with the recombinant protein or with the lysates of tumor cells. The high frequency of responders (i.e., immunoprevalence) was provided by a wide reactivity of multiple peptides. Six peptides were T cell stimulating in at least half of the donors and were close to CD8⁺ T cell epitopes. HLA-DR molecules were more frequently involved in T cell stimulation than were HLA-DP4 molecules, and hence immunoprevalence relies mainly on HLA-DR promiscuity in the survivin Ag. In two cancer patients a spontaneous CD4⁺ T cell response specific for one of these peptides was also observed. Based on these observations, the tumor-shared survivin does not appear to be the target of immune tolerance in healthy donors and cancer patients and is a relevant candidate for cancer vaccine.

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 Commissariat à l'Energie Atoand grants from l'Institut National du Cancer, Ligue Contre le Cancer du Val de Marne, Pole de Compétitivité Ile de France: Projet Immucan, Centre d'Investigation Clinique en Biothérapie (Assistance Publique-Hôpitaux de Paris/Institut National de la Santé et de la Recherche Médicale), Grant EEC No. LSHC-2005-518234, "Cancer Immunotherapy".

² Address correspondence and reprint requests to Dr. Bernard Maillere, Commissariat à l'Energie Atomique, Institut de Biologie et Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéines, Gif Sur Yvette, F-91191, France. E-mail address: bernard.maillere{at}cea.fr

³ Abbreviations used in this paper: HLA II, HLA class II; DC, dendritic cell; NSLC, non-small cell lung carcinoma; RCC, renal cell carcinoma; rh, recombinant human.