Triple expression of B7-1, B7-2 and 4-1BBL enhanced antitumor immune response against mouse H22 hepatocellular carcinoma.
OBJECTIVE
Costimulatory signals are essential for T-cell activation and hence play a very important role in antitumor immunity. B7 and 4-1BBL which belongs to tumor necrosis factor (TNF) family provide costimulatory interaction for T-cell activation and function. This study investigated the role of B7 and 4-1BBL in the amplification of tumor immunity by transduction of the B7-1, B7-2 and 4-1BBL into mouse hepatocellular carcinoma cell line H22.


METHODS
The tumorigenicity of H22 variants expressing either B7-1, B7-2 (H22/B7-1/B7-2) or 4-1BBL was compared with an H22 variant expressing B7-1, B7-2 and 4-1BBL (H22/B7-1/B7-2/4-1BBL). The study next investigated whether the combination of B7-1/B7-2 and 4-1BBL cell injection induced cytotoxic T lymphocyte (CTL) response and IL-2/IFN-γ secretion. The immune mechanisms underlying this combination treatment were then analyzed.


RESULTS
Syngeneic BALB/c mice injected with H22/B7-1/B7-2/4-1BBL cells that expressed elevated levels of B7-1, B7-2 and 4-1BBL showed a tumor development frequency of 50% compared with 100% in mice injected with the H22 parental line, H22/neo, H22/B7-1/B7-2 and H22/4-1BBL. Mice inoculated with H22 tumor cells expressing B7-1, B7-2 and 4-1BBL developed a strong cytotoxic T lymphocyte response and long-term immunity against wild-type tumor, suggesting a synergistic effect between the B7 and 4-1BBL costimulatory pathways. Results showed that H22/B7-1/B7-2/4-1BBL tumor vaccines probably protect the infiltrating lymphocytes from apoptosis and induce NF-κB activation to improve T-cell-mediated antitumor response.


CONCLUSIONS
In this study, the antitumor consequences of using B7-1, B7-2 and 4-1BBL gene transfer have demonstrated the therapeutic potential of gene therapy approach for hepatocellular carcinoma.
Li
Guoqiang
G
Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
Wu
Xiaofeng
X
Zhang
Feng
F
Li
Xiangcheng
X
Sun
Beicheng
B
Yu
Yue
Y
Yin
Aihong
A
Deng
Lei
L
Yin
Jie
J
Wang
Xuehao
X
D053330:4-1BB Ligand / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D018122:B7-1 Antigen / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051940:B7-2 Antigen / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D053330:4-1BB Ligand; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D007376:Interleukin-2; D016328:NF-kappa B; D007371:Interferon-gamma