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 patients.
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.
Commissariat à l'Energie Atomique, Institut de Biologie et Technologies de Saclay, Service d'Ingénierie Moléculaire des Protéine, Gif Sur Yvette, Paris, France.
Xiao-Fei
XF
Wang
Jerome
J
Kerzerho
Olivier
O
Adotevi
Hélène
H
Nuyttens
Cecile
C
Badoual
Gaetan
G
Munier
Stéphane
S
Oudard
Shuiping
S
Tu
Eric
E
Tartour
Bernard
B
Maillère
D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology; D006682:HLA-DP Antigens / Q000276:immunology*; D059868:HLA-DP beta-Chains; D006684:HLA-DR Antigens / Q000276:immunology*; D006262:Health; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D000077022:Survivin
D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C056284:HLA-DPw4 antigen; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin