Ii-Key/HER-2/neu(776-790) hybrid peptides induce more effective immunological responses over the native peptide in lymphocyte cultures from patients with HER-2/neu+ tumors.
We have demonstrated that coupling an immunoregulatory segment of the MHC class II-associated invariant chain (Ii), the Ii-Key peptide, to a promiscuous MHC class II epitope significantly enhances its presentation to CD4+ T cells. Here, a series of homologous Ii-Key/HER-2/neu(776-790) hybrid peptides, varying systematically in the length of the epitope(s)-containing segment, are significantly more potent than the native peptide in assays using T cells from patients with various types of tumors overexpressing HER-2/neu. In particular, priming normal donor and patient PBMCs with Ii-Key hybrid peptides enhances recognition of the native peptide either pulsed onto autologous dendritic cells (DCs) or naturally presented by IFN-gamma-treated autologous tumor cells. Moreover, patient-derived CD4+ T cells primed with the hybrid peptides provide a significantly stronger helper effect to autologous CD8+ T cells specific for the HER-2/neu(435-443) CTL epitope, as illustrated by either IFN-gamma ELISPOT assays or specific autologous tumor cell lysis. Hybrid peptide-specific CD4+ T cells strongly enhanced the antitumor efficacy of HER-2/neu(435-443) peptide-specific CTL in the therapy of xenografted SCID mice inoculated with HER-2/neu overexpressing human tumor cell lines. Our data indicate that the promiscuously presented vaccine peptide HER-2/neu(776-790) is amenable to Ii-Key-enhancing effects and supports the therapeutic potential of vaccinating patients with HER-2/neu+ tumors with such Ii-Key/HER-2/neu(776-790) hybrid peptides.
Sotiriadou
Nectaria N
NN
Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
Kallinteris
Nikoletta L
NL
Gritzapis
Angelos D
AD
Voutsas
Ioannis F
IF
Papamichail
Michael
M
von Hofe
Eric
E
Humphreys
Robert E
RE
Pavlis
Theodoros
T
Perez
Sonia A
SA
Baxevanis
Constantin N
CN
D017951:Antigen Presentation / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000944:Antigens, Differentiation, B-Lymphocyte; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; C045084:invariant chain