title: Streptococcal preparation OK-432 promotes fusion efficiency and enhances induction of antigen-specific CTL by fusions of dendritic cells and colorectal cancer cells.
abstract: Dendritic/tumor fusion cell (FC) vaccine is an effective approach for various types of cancer but has not yet been standardized. Antitumor activity can be modulated by different mechanisms such as dendritic cell (DC) maturation state. This study addressed optimal strategies for FC preparations to enhance Ag-specific CTL activity. We have created three types of FC preparations by alternating fusion cell partners: 1) immature DCs fused with autologous colorectal carcinoma cells (Imm-FCs); 2) Imm-FCs followed by stimulation with penicillin-inactivated Streptococcus pyogenes (OK-432) (Imm-FCs/OK); and 3) OK-432-stimulated DCs directly fused to autologous colorectal carcinoma cells (OK-FCs). Both OK-FCs and Imm-FCs/OK coexpressed the CEA, MUC1, and significantly higher levels of CD86, CD83, and IL-12 than those obtained with Imm-FCs. Short-term culture of fusion cell preparations promoted the fusion efficiency. Interestingly, OK-FCs were more efficient in stimulating CD4(+) and CD8(+) T cells capable of high levels of IFN-gamma production and cytolysis of autologous tumor or semiallogeneic targets. Moreover, OK-FCs are more effective inducer of CTL activation compared with Imm-FCs/OK on a per fusion cell basis. The pentameric assay confirmed that CEA- and MUC1-specific CTL was induced simultaneously by OK-FCs at high frequency. Furthermore, the cryopreserved OK-FCs retained stimulatory capacity for inducing antitumor immunity. These results suggest that OK-432 promotes fusion efficiency and induction of Ag-specific CTL by fusion cells. We conclude that DCs fused after stimulation by OK-432 may have the potential applicability to the field of antitumor immunotherapy and may provide a platform for adoptive immunotherapy in the clinical setting.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Jikei University School of Medicine, Tokyo, Japan. shigeo_koido@jikei.ac.jp
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koido
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hara
authors.forename: Sadamu
authors.initials: S
authors.lastname: Homma
authors.forename: Akira
authors.initials: A
authors.lastname: Torii
authors.forename: Makoto
authors.initials: M
authors.lastname: Mitsunaga
authors.forename: Satoru
authors.initials: S
authors.lastname: Yanagisawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Toyama
authors.forename: Hidejiro
authors.initials: H
authors.lastname: Kawahara
authors.forename: Michiaki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Seiya
authors.initials: S
authors.lastname: Yoshida
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanaga
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Fujise
authors.forename: Hisao
authors.initials: H
authors.lastname: Tajiri
mesh_terms: D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051940:B7-2 Antigen / Q000032:analysis / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D002272:Carcinoembryonic Antigen / Q000032:analysis / Q000378:metabolism; D002459:Cell Fusion / Q000379:methods*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis / Q000378:metabolism; D007371:Interferon-gamma / Q000032:analysis / Q000378:metabolism; D016753:Interleukin-10 / Q000032:analysis / Q000378:metabolism; D018664:Interleukin-12 / Q000032:analysis / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism; D018396:Mucin-1 / Q000378:metabolism; D010844:Picibanil / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D051940:B7-2 Antigen; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D007136:Immunoglobulins; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D018396:Mucin-1; D010844:Picibanil; D000097802:CD83 Antigen