Tumor-derived TGF-beta reduces the efficacy of dendritic cell/tumor fusion vaccine.
Dendritic cell (DC)-based antitumor vaccine is a novel cancer immunotherapy that is promising for reducing cancer-related mortality. However, results from early clinical trials were suboptimal. A possible explanation is that many tumors secrete immunosuppressive factors such as TGF-beta, which may hamper host immune response to DC vaccine. In this study, we demonstrated that TGF-beta produced by tumors significantly reduced the potency of DC/tumor fusion vaccines. TGF-beta-secreting (CT26-TGF-beta) stable mouse colon cancer cell lines were generated using a retroviral vector expressing TGF-beta. A non-TGF-beta-secreting (CT26-neo) cell line was generated using an empty retroviral vector. The efficacies of DC/tumor fusion vaccines were assessed in vitro and in vivo. DC/CT26-TGF-beta fusion cells failed to induce a strong T cell proliferative response in vitro, mainly due to the effect of TGF-beta on T cell responsiveness rather than DC stimulatory capability. Animals vaccinated with DC/CT26-TGF-beta fusion vaccine had lower tumor-specific CTL activity and had significantly lower survival after tumor challenge as compared with animals immunized with DC/CT26-neo hybrids (45 vs 77%, p < 0.05). Ex vivo exposure of DCs to TGF-beta did not appear to lessen the efficacy of DC vaccine. These data suggest that tumor-derived TGF-beta reduces the efficacy of DC/tumor fusion vaccine via an in vivo mechanism. Neutralization of TGF-beta produced by the fusion cells may enhance the effectiveness of DC-based immunotherapy.
Kao
John Y
JY
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0650, USA.
Gong
Yusong
Y
Chen
Chuan-Min
CM
Zheng
Qiong-Duan
QD
Chen
Jian-Jun
JJ
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology; D002458:Cell Fractionation; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D005260:Female; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000009:adverse effects* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D013491:Suppressor Factors, Immunologic / Q000009:adverse effects* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology
D019496:Cancer Vaccines; D009363:Neoplasm Proteins; D013491:Suppressor Factors, Immunologic; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014614:Vaccines, Synthetic