Immunological properties and vaccine efficacy of murine dendritic cells simultaneously expressing melanoma-associated antigen and interleukin-12

• Published in: Cancer gene therapy Vol. 12; no. 1; pp. 72 - 83
• Main Authors: Okada, Naoki, Iiyama, Sayaka, Okada, Yuka, Mizuguchi, Hiroyuki, Hayakawa, Takao, Nakagawa, Shinsaku, Mayumi, Tadanori, Fujita, Takuya, Yamamoto, Akira
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.01.2005
• Subjects: Adenoviridae - genetics; Adenovirus; Animals; Antigens, Neoplasm; Antigens, Surface; Cancer Vaccines; Control; Dendritic cells; Dendritic Cells - immunology; Female; Genetic aspects; Genetic Engineering; Interleukin-12; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Melanoma; Melanoma - immunology; Melanoma-Specific Antigens; Mice; Mice, Inbred C57BL; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Physiological aspects; T-Lymphocytes, Cytotoxic; Transduction, Genetic; Tumor Cells, Cultured; Up-Regulation; Japan
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/sj.cgt.7700772

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.