Immunological properties and vaccine efficacy of murine dendritic cells simultaneously expressing melanoma-associated antigen and interleukin-12.
Interleukin (IL)-12 is a key factor for inducing cellular immune responses, which play a central role in the eradication of cancer. In the present study, in order to create a dendritic cell (DC)-based vaccine capable of positively skewing immune response toward a cellular immunity-dominant state, we analyzed immunological characteristics and vaccine efficacy of DCs cotransduced with melanoma-associated antigen (gp100) and IL-12 gene (gp100+IL12/DCs) by using RGD fiber-mutant adenovirus vector (AdRGD), which enables highly efficient gene transduction into DCs. gp100+IL12/DCs could simultaneously express cytoplasmic gp100 and secretory IL-12 at levels comparable to DCs transduced with each gene alone. In comparison with DCs transduced with gp100 alone (gp100/DCs), upregulation of major histocompatibility complex class I, CD40, and CD86 molecules on the cell surface and more potent T-cell-stimulating ability for proliferation and interferon-gamma secretion were observed as characteristic changes in gp100+IL12/DCs. In addition, administration of gp100+IL12/DCs, which were prepared by a relatively low dose of AdRGD-IL12, could induce more potent tumor-specific cellular immunity in the murine B16BL6 melanoma model than vaccination with gp100/DCs. However, antitumor effect and B16BL6-specific cytotoxic T-lymphocyte activity in mice vaccinated with gp100+IL12/DCs diminished with increasing AdRGD-IL12 dose during gene transduction, and paralleled the decrease in presentation levels via MHC class I molecules for antigen transduced with another AdRGD. Collectively, our results suggested that optimization of combined vector dose was required for development of a more efficacious DC-based vaccine for cancer immunotherapy, which relied on genetic engineering to simultaneously express tumor-associated antigen and IL-12.
Okada
Naoki
N
Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan. okada@mb.kyoto-phu.ac.jp
Iiyama
Sayaka
S
Okada
Yuka
Y
Mizuguchi
Hiroyuki
H
Hayakawa
Takao
T
Nakagawa
Shinsaku
S
Mayumi
Tadanori
T
Fujita
Takuya
T
Yamamoto
Akira
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D019496:Cancer Vaccines; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005818:Genetic Engineering; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics*; D008545:Melanoma / Q000276:immunology*; D058950:Melanoma-Specific Antigens; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D019496:Cancer Vaccines; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D018664:Interleukin-12