title: Induction of potent CD4+ T cell-mediated antitumor responses by a helper HER-2/neu peptide linked to the Ii-Key moiety of the invariant chain.
abstract: The Ii-Key fragment from the MHC class II-associated invariant chain (or Ii protein) has been shown to facilitate direct charging of MHC class II epitopes to the peptide binding groove. The purpose of the present study was to test the potential of a series of Ii-Key/HER-2/neu776-790 hybrid peptides to generate increased frequencies of peptide-specific CD4+ T cells over the native peptide in mice transgenic (Tg) for a chimeric human mouse class II molecule (DR4-IE) (H-2b) as well as their antitumor potency. Following in vivo priming, such hybrid peptides induced increased proliferation and frequencies of IFN-gamma producing CD4+ T cells in response to either syngeneic dendritic cells pulsed with native peptide, or HLA-DR4+ human tumor cell lines expressing HER-2/neu. Hybrid peptides were more stable in an off-rate kinetics assay compared to the native peptide. In addition, antigen-specific CD4+ T cells from hybrid peptide immunized DR4-IE Tg mice synergized with HER-2/neu(435-443)-specific CD8+ T cells from HLA-A2.1 Tg HHD (H-2b) mice in producing antitumor immunity into SCID mice xenografted with the HER-2/neu+, HLA-A2.1+ and HLA-DR4+ FM3 human melanoma cell line. High proportions of these adoptively transferred HER-2/neu peptide-specific CD4+ and CD8+ T cells infiltrated FM3-induced tumors (tumor infiltrating lymphocytes; TIL) in SCID mice. CD8+ TIL exhibited long-lasting antitumor activity when cotransferred with CD4+ TIL, inducing regression of FM3 tumors in a group of untreated, tumor-bearing SCID mice, following adoptive transfer. Our data show that Ii-Key modified HER-2/neu776-790 hybrid peptides are sufficiently potent to provide antigen-specific CD4+ TH cells with therapeutic antitumor activity.
authors.affiliation: Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
authors.forename: Ioannis F
authors.initials: IF
authors.lastname: Voutsas
authors.affiliation: Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
authors.forename: Angelos D
authors.initials: AD
authors.lastname: Gritzapis
authors.affiliation: Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
authors.forename: Louisa G
authors.initials: LG
authors.lastname: Mahaira
authors.affiliation: Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Salagianni
authors.affiliation: Antigen Express Inc., Biotech III, One Innovation Drive, Worcester, MA.
authors.forename: Eric von
authors.initials: EV
authors.lastname: Hofe
authors.affiliation: Antigen Express Inc., Biotech III, One Innovation Drive, Worcester, MA.
authors.forename: Nikoletta L
authors.initials: NL
authors.lastname: Kallinteris
authors.affiliation: Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
authors.forename: Constantin N
authors.initials: CN
authors.lastname: Baxevanis
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C524356:HER-2 protein (435-443); C524355:HER-2 protein (776-790); C045084:invariant chain