Presentation of a major histocompatibility complex class 1-binding peptide by monocyte-derived dendritic cells incorporating hydrophobized polysaccharide-truncated HER2 protein complex: implications for a polyvalent immuno-cell therapy.
Recognition of the essential role of dendritic cells (DCs) as professional antigen-presenting cells has prompted investigators to search for methods to use DCs as natural adjuvants in immunotherapy. A number of antigenic oligopeptides, recognized by CD8(+) cytotoxic T lymphocytes (CTLs) specific for cancer cells, have been applied in clinical trials using DCs. Such a monovalent vaccine with a single epitope for a particular type of HLA class 1 molecule would be effective. However, a polyvalent vaccine might be more potent. We designed a novel protein delivery system consisting of hydrophobized polysaccharides complexed with target proteins. The truncated HER2 protein encompassing 147 N-terminal amino acids, including the 9-mer HER2p63-71 peptide (HER2p63), TYLPTNASL, the human homologue of an antigenic murine tumor rejection peptide, was prepared. We report here that HLA-A2402(+) DCs could incorporate hydrophobized polysaccharide-truncated HER2 protein complexes and process the protein to present major histocompatibility complex class 1-binding HER2p63 peptide. The complexes enter DCs by phagocytosis, and then the truncated protein is processed through a pathway similar to that for endogenous proteins. DCs sensitized by these complexes primed and boosted HER2p63-specific CD8(+) T cells in the context of HLA-A2402. Vaccination with DCs incorporating these complexes completely suppressed lung metastases in a HER2-expressing murine tumor model. We also generated 3 CD4(+) clones reactive with different HER2- derived 25-mer peptides from lymph node cells in mice treated with CHP/HER2-147. Thus, hydrophobized polysaccharide-protein complexes are promising candidates for the construction of polyvalent vaccines.
Ikuta
Yasushi
Y
Second Department of Internal Medicine, the Department of Obstetrics and Gynecology, Mie University School of Medicine, Tsu, Japan.
Katayama
Naoyuki
N
Wang
Lijie
L
Okugawa
Toshiharu
T
Takahashi
Yoshiyuki
Y
Schmitt
Michael
M
Gu
Xiaogang
X
Watanabe
Masato
M
Akiyoshi
Kazunari
K
Nakamura
Hideo
H
Kuribayashi
Kagemasa
K
Sunamoto
Junzo
J
Shiku
Hiroshi
H
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002478:Cells, Cultured; D002999:Clone Cells; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005936:Glucans / Q000737:chemistry; D015234:HLA-A Antigens / Q000378:metabolism; D059871:HLA-A24 Antigen; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D046911:Macromolecular Substances; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D005936:Glucans; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D046911:Macromolecular Substances; D010446:Peptide Fragments; D011134:Polysaccharides; D018719:Erb-b2 Receptor Tyrosine Kinases; C455902:HER2p63 peptide; C438506:HLA-A*24:02 antigen; C009109:pullulan