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

1区 · 医学

Article

作者: Watanabe, Masato ; Gu, Xiaogang ; Ikuta, Yasushi ; Katayama, Naoyuki ; Wang, Lijie ; Nakamura, Hideo ; Kuribayashi, Kagemasa ; Shiku, Hiroshi ; Takahashi, Yoshiyuki ; Akiyoshi, Kazunari ; Okugawa, Toshiharu ; Sunamoto, Junzo ; Schmitt, Michael

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.

2000-07-19·Cancer Chemotherapy and Pharmacology4区 · 医学

Development of a cancer vaccine: peptides, proteins, and DNA

4区 · 医学

Article

作者: Toshiharu Okugawa ; Xiaogang Gu ; Junzo Sunamoto ; Kazunari Akiyoshi ; Hideo Nakamura ; Yasushi Ikuta ; Lijie Wang ; Michael Schmitt ; Hiroshi Shiku

Genetic changes leading to protooncogene activation qualitatively and/or quantitatively alter their gene products and are exclusively or largely restricted to transforming cells and their precursors. The overexpression of HER2 is among those changes and is often detected in adenocarcinomas such as breast, ovarian, lung, and gastric cancer. This provides a rationale for exploring the possibility that HER2 is a target of host immune responses against cancer cells. We have recently demonstrated that HER2 can be a target for tumor-rejecting immune responses against syngeneic murine HER2+ tumor cells. We defined two different peptides, HER2p63-71 and HER2p780-788, with a Kd anchor motif that can induce CD8+ cytotoxic T lymphocytes (CTLs). The growth of HER2+ syngeneic tumors was suppressed in mice immunized with HER2p63-71 or p780-788. Since murine Kd and human HLA-A24 share a similar anchor motif for peptides, HER2p63 71 and HER2p780-788 were examined for induction of CTLs in HLA-A24+ individuals. CD8+ CTL clones specific for these peptides were established and they lysed HER2+ tumor cells in a human leukocyte antigen (HLA)-A24-restricted manner. To elicit specific CD8+ T cell immune responses against cancer, the development of efficient devices to deliver tumor antigen peptides to the major histocompatibility complex (MHC) class I pathway constitutes a central issue. We have developed a novel formula of hydrophobized polysaccharide nanoparticles which can deliver a HER2 oncoprotein containing an epitope peptide to the MHC class I pathway. We designed a simple protein delivery system: cholesteryl group-bearing polysaccharides, mannan or pullulan (CHM or CHP, respectively), complexed with the truncated HER2 protein containing the 147 N-terminal amino acids. These complexes were able to induce CD8+ CTLs against HER2+ tumors. CTLs were MHC class I restricted and specifically recognized HER2p63-71, a part of a truncated HER2 protein used as an immunogen. The complete rejection of tumors also occurred when CHM-HER2 was applied early after tumor implantation. In the effector phase of in vivo tumor rejection, CD8+ T cells played a major role. The results suggest that this unique hydrophobized polysaccharide may help soluble proteins to induce cellular immunity. Such a novel vaccine may be of potential benefit in cancer prevention and cancer therapy.

100 项与 HER2p63-71 peptide vaccine(Mie University) 相关的药物交易

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