Intratumoral administration of immature dendritic cells following the adenovirus vector encoding CD40 ligand elicits significant regression of established myeloma.
Our previous study showed that J558 myeloma cells engineered CD40L lost their tumorigenicity in syngeneic mice, and the inoculation of J558/CD40L tumor cells further led to the protective immunity against wild tumors. In the present study, we investigated whether the vaccine can exert more efficient antitumor immunity by combination with adenovirus mediated CD40L gene therapy and immature dendritic cells (iDCs). The results demonstrated that intratumoral administration of iDCs 2 days after AdVCD40L injection, not only significantly suppressed the tumor growth, but also eradiated the established tumors in 40% of the mice. The potent antitumor effect produced by the combination therapy correlated with high expression of MHC, costimulatory and Fas molecules on J558 cells, which was derived from CD40L transgene expression. In addition, transgene CD40L expression could dramatically induce J558 cell apoptosis. Effectively capturing apoptotic bodies by iDCs in vivo could induce DC maturation, prime tumor-specific CTLs and tend to Th1-type immune response. Finally, in vivo depletion experimentation suggested both CD4+ and CD8+ T cells were involved in mediating the antitumor immune responses of combined treatment of AdVCD40L and iDCs, with CD8+ T cells being the major effector. These findings could be beneficial for designing strategies of DCs vaccine and CD40L for anticancer immunotherapy.
Liu
Yongqing
Y
Research Unit, Saskatchewan Cancer Agency and Departments of Microbiology, Immunology and Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0W0.
Xia
Dajing
D
Li
Fang
F
Zheng
Changyu
C
Xiang
Jim
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D023201:CD40 Ligand / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000627:therapeutic use; D018920:Coculture Techniques; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic; D019076:Transgenes / Q000502:physiology; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D019496:Cancer Vaccines; D023201:CD40 Ligand