Interleukin-12-gene transduction makes DCs from tumor-bearing mice an effective inducer of tumor-specific immunity in a peritoneal dissemination model.
Dendritic cells (DCs) from cancer patients, as well as tumor-infiltrating DCs, are reported to have suppressed immunostimulatory capacity. One of the major problems in the clinical use of DCs for treating tumors is that the DCs must be autologous ones obtained from patients. Compared with normal DCs (nDCs), flow-cytometric analysis and allogeneic mixed lymphocyte reaction (MLR) have revealed lower expression of the costimulatory molecules and suppressed T-cell-stimulatory activity in DCs derived from tumor-bearing mice (tDCs) despite of culture. We reported previously that the interleukin-12 (IL-12)-gene-transduced nDCs inhibited tumor growth due to induced tumor-specific Th1 and cytotoxic T cells (CTLs) in a murine established subcutaneous tumor model. In the present study, we examined whether tDCs could induce immune responses against tumors after IL-12-gene transduction in an established peritoneal dissemination model. The intraperitoneal injection of IL-12-gene-transduced tDCs resulted in prolonged survival of some treated mice (log-rank test; P=0.001) and tumor-specific Th1 and CTL activity. The injection of IL-12-gene-transduced nDCs prolonged the survival of all treated mice (P<0.0001) and elicited tumor-specific immunity, which were better than those of IL-12-gene-transduced tDCs. Taken together, DC modification of IL-12-gene transduction is an effective and promising approach for cancer therapy even when immunosuppressive tDCs are employed.
Furumoto
Katsuyoshi
K
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. furumoto@stanford.edu
Mori
Akira
A
Yamasaki
Seiji
S
Inoue
Naoya
N
Yang
Weige
W
Nakau
Masayuki
M
Yasuda
Seiichi
S
Arii
Shigeki
S
Imamura
Masayuki
M
D000230:Adenocarcinoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D015316:Genetic Therapy; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma