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.
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.
Voutsas
Ioannis F
IF
Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
Gritzapis
Angelos D
AD
Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
Mahaira
Louisa G
LG
Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
Salagianni
Maria
M
Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
Hofe
Eric von
EV
Antigen Express Inc., Biotech III, One Innovation Drive, Worcester, MA.
Kallinteris
Nikoletta L
NL
Antigen Express Inc., Biotech III, One Innovation Drive, Worcester, MA.
Baxevanis
Constantin N
CN
Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece.
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
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