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

• Published in: Blood Vol. 99; no. 10; pp. 3717 - 3724
• Main Authors: Ikuta, Yasushi, Katayama, Naoyuki, Wang, Lijie, Okugawa, Toshiharu, Takahashi, Yoshiyuki, Schmitt, Michael, Gu, Xiaogang, Watanabe, Masato, Akiyoshi, Kazunari, Nakamura, Hideo, Kuribayashi, Kagemasa, Sunamoto, Junzo, Shiku, Hiroshi
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-05-2002; The Americain Society of Hematology
• Subjects: Amino Acid Sequence; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antigen Presentation; Antigens, Neoplasm - chemistry; Antigens, Neoplasm - immunology; Applied cell therapy and gene therapy; Biological and medical sciences; Cancer Vaccines - immunology; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Clone Cells; Dendritic Cells - immunology; Female; Glucans - chemistry; HLA-A Antigens - metabolism; HLA-A24 Antigen; Humans; Hydrophobic and Hydrophilic Interactions; Macromolecular Substances; Medical sciences; Mice; Mice, Inbred BALB C; Monocytes - immunology; Neoplasms - immunology; Neoplasms - therapy; Peptide Fragments - chemistry; Peptide Fragments - immunology; Peptide Fragments - metabolism; Polysaccharides - chemistry; Receptor, ErbB-2 - chemistry; Receptor, ErbB-2 - immunology; Receptor, ErbB-2 - metabolism; T-Lymphocytes, Cytotoxic - immunology; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Antineoplastic agent; Pulsed dendritic cell; Dendritic cell; Antigen presentation; HLA-System; Cell therapy; Antigenic determinant; Major histocompatibility system; Rodentia; Malignant tumor; Polyvalent vaccine; Vertebrata; Mammalia; Treatment; Mouse; Antigen presenting cell; Immunological adjuvant; Animal; Immunotherapy; HER2 protein; Polysaccharide; Class I histocompatibility antigen
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V99.10.3717

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.