Synergistic induction of antigen-specific CTL by fusions of TLR-stimulated dendritic cells and heat-stressed tumor cells.
Dendritic cell (DC)/tumor cell fusion cells (FCs) can induce potent CTL responses. The therapeutic efficacy of a vaccine requires the improved immunogenicity of both DCs and tumor cells. The DCs stimulated with the TLR agonist penicillin-killed Streptococcus pyogenes (OK-432; OK-DCs) showed higher expression levels of MHC class I and II, CD80, CD86, CD83, IL-12, and heat shock proteins (HSPs) than did immature DCs. Moreover, heat-treated autologous tumor cells displayed a characteristic phenotype with increased expression of HSPs, carcinoembryonic Ag (CEA), MUC1, and MHC class I (HLA-A2 and/or A24). In this study, we have created four types of FC preparation by alternating fusion cell partners: 1) immature DCs fused with unheated tumor cells; 2) immature DCs fused with heat-treated tumor cells; 3) OK-DCs fused with unheated tumor cells; and 4) OK-DCs fused with heat-treated tumor cells. Although OK-DCs fused with unheated tumor cells efficiently enhanced CTL induction, OK-DCs fused with heat-treated tumor cells were most active, as demonstrated by: 1) up-regulation of multiple HSPs, MHC class I and II, CEA, CD80, CD86, CD83, and IL-12; 2) activation of CD4+ and CD8+ T cells able to produce IFN- gamma at higher levels; 3) efficient induction of CTL activity specific for CEA or MUC1 or both against autologous tumor; and 4) superior abilities to induce CD107+ IFN-gamma+ CD8+ T cells and CD154+ IFN-gamma+ CD4+ T cells. These results strongly suggest that synergism between OK-DCs and heat-treated tumor cells enhances the immunogenicity of FCs and provides a promising means of inducing therapeutic antitumor immunity.
Koido
Shigeo
S
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. shigeo_koido@jikei.ac.jp
Hara
Eiichi
E
Homma
Sadamu
S
Mitsunaga
Makoto
M
Takahara
Akitaka
A
Nagasaki
Eijiro
E
Kawahara
Hidejiro
H
Watanabe
Michiaki
M
Toyama
Yoichi
Y
Yanagisawa
Satoru
S
Kobayashi
Susumu
S
Yanaga
Katsuhiko
K
Fujise
Kiyotaka
K
Gong
Jianlin
J
Tajiri
Hisao
H
D000941:Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006358:Hot Temperature; D006801:Humans; D006822:Hybrid Cells; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism*
D000941:Antigens; D018840:HSP70 Heat-Shock Proteins; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma