A new strategy for cancer immunotherapy using dendritic cell-macrophage hybrids

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 16390313
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: University of Yamanashi
• Principal Investigator: MATSUE Hiroyuki University of Yamanashi, Department of Research, Interdisciplinary Graduate School of Medicine and Engineering, Associate Professor, 大学院・医学工学総合研究部, 助教授 (10250424)
• Co-Investigator(Kenkyū-buntansha): SHIBAGAKI Naotaka University of Yamanashi, University of Yamanashi Hospital, Assistant Professor, 医学部附属病院, 講師 (40262662)
• Project Period (FY): 2004 – 2005
• Keywords: Dendritic cells / Macrophage / Cell fusion / Hybrid cells / Tumor immunity / Immunotherapy / Gap junction / Connexin

Research Abstract

Dendritic cells (DC) are special subsets of antigen presenting cells (APC) characterized by their strong abilities to induce acquired immunity including anti-tumor immunity and by their weak abilities to directly (i.e., cytotoxic capability) and/or indirectly (via ADCC) kill harmful cells (e.g., tumor cells). Conversely, macrophages (mΦ) serve as weak APC and cells possessing ADCC. Our hypothesis was that DC-mΦ hybrids may overcome each weakness and exert beneficial and strong anti-tumor immunity. To test this hypothesis, we first established a new strategy to select only hybrid cells by our double-selection method. Second, using this selection method, we fused DC and mΦ, and then established hybrids were examined for their phenotypes. We found difficulties to distinguish these two cell types by functional and surface phenotypes and also found heterogeneity between hybrid clones (Matsue H, et al., Cancer Biology & Therapy, 3:1145-1151, 2004). During a series of hybrid experiments, we r ealized that DC were activated by cell fusion at extremely high cell density. We shifted our research focus to figure out the reason for their activation and found that DC are activated via gap junctions during cell fusion. As a by-product of this project, we discovered that gap junction-mediated intercellular communication (GJIC) between DC is required for effective activation of DC. (Matsue H, et al., J Immunol. 176:181-190, 2006). We believe that harness of GJIC between DC may become a new strategy to induce or silence the immunity for new therapeutic modalities.
In summary, although we failed to develop a new strategy for anti-cancer therapy using DC-mΦ hybrids, our fusion method formed the technical basis for generation of artificial new immune cells that have two totally different immunological functions. This strategy will provide a new avenue for cell-based immunotherapies. In addition, pharmacological manipulation of GJIC will provide another direction of DC research to control the immunity.

Research Products

• [Journal Article] Gap junction-mediated intercellular communication between dendritic cells (DCs) is required for effective activation of DCs (2006)
  • Author(s): Matsue, H., Yao, J., Matsue, K., Nagasaka, A., Sugiyama, H., Aoki, R., Kitamura, M., Shimada, S.
  • Journal Title: J. Immunol. 176・1 Pages: 181-190
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gap junction-mediated intercellular communication between dendritic cells (DCs) is required for effective activation of DCs. (2006)
  • Author(s): Matsue, H., Yao, J., Matsue, K., Nagasaka, A., Sugiyama, H., Aoki, R., Kitamura, M., Shimada, S.
  • Journal Title: J.Immunol. 176(1) Pages: 181-190
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Limitations of CD95 ligand-transduced killer dendritic cells to prevent graft rejections. (2005)
  • Author(s): Kusuhara, M., Matsue, H.
  • Journal Title: Exp. Dermatol. 14・4 Pages: 273-280
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential activation profiles of multiple transcription factors during dendritic cell maturation. (2005)
  • Author(s): Mizumoto, N., Hui, F., Edelbaum, D., Weil, M.R., Wren, J.D., Shalhevet, D., Matsue, H., Liu, L., Garner, H.R., Takashima A.
  • Journal Title: J. Invest. Dermatol. 124・4 Pages: 718-724
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] CD200-mediated regulation of skin immunity. (2005)
  • Author(s): Matsue, H.
  • Journal Title: J. Invest. Dermatol. 125・6 Pages: x-xi
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Limitations of CD95 ligand-transduced killer dendritic cells to prevent graft rejections. (2005)
  • Author(s): Kusuhara, M., Matsue, H.
  • Journal Title: Exp.Dermatol. 14(4) Pages: 273-280
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Differential activation profiles of multiple transcription factors during dendritic cell maturation. (2005)
  • Author(s): Mizumoto, N., Hui, F., Edelbaum, D., Weil, M.R., Wren, J.D., Shalhevet, D., Matsue, H., Liu, L., Garner, H.R., Takashima A.
  • Journal Title: J.Invest.Dermatol. 124(4) Pages: 718-724
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CD200-mediated regulation of skin immunity. (2005)
  • Author(s): Matsue, H.
  • Journal Title: J.Invest.Dermatol. 125(6) Pages: x-xi
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] New strategy for efficient selection of dendritic cell-tumor hybrids and clonal heterogeneity of resulting hybrids. (2004)
  • Author(s): Matsue, H., Matsue, K., Edelbaum, D., Walters, M., Morita, A., Takashima, A.
  • Journal Title: Cancer Biol. Ther. 3・11 Pages: 1145-1151
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] New strategy for efficient selection of dendritic cell-tumor hybrids and clonal heteroigeneity of resulting hybrids. (2004)
  • Author(s): Matsue, H., Matsue, K., Edelbaum, D., Walters, M., Morita, A., Takashima, A.
  • Journal Title: Cancer Biol.Ther. 3(11) Pages: 1145-1151
  • Description: 「研究成果報告書概要(欧文)」より