Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Cancer Vaccines / administration & dosage
-
Cancer Vaccines / adverse effects*
-
Cancer Vaccines / genetics
-
Cancer Vaccines / immunology
-
Cell Fractionation
-
Cell-Free System / immunology
-
Cell-Free System / metabolism
-
Coculture Techniques
-
Cytotoxicity, Immunologic / genetics
-
Dendritic Cells / immunology
-
Dendritic Cells / transplantation*
-
Female
-
Injections, Intraperitoneal
-
Lymphocyte Activation / genetics
-
Mice
-
Mice, Inbred BALB C
-
Neoplasm Proteins / adverse effects*
-
Neoplasm Proteins / blood
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism
-
Neoplasms, Experimental / immunology*
-
Neoplasms, Experimental / metabolism
-
Neoplasms, Experimental / mortality
-
Neoplasms, Experimental / prevention & control*
-
Suppressor Factors, Immunologic / adverse effects*
-
Suppressor Factors, Immunologic / blood
-
Suppressor Factors, Immunologic / genetics
-
Suppressor Factors, Immunologic / metabolism
-
T-Lymphocyte Subsets / immunology
-
T-Lymphocytes, Cytotoxic / immunology
-
Transforming Growth Factor beta / administration & dosage
-
Transforming Growth Factor beta / adverse effects*
-
Transforming Growth Factor beta / blood
-
Transforming Growth Factor beta / metabolism
-
Transforming Growth Factor beta1
-
Tumor Cells, Cultured / immunology
-
Tumor Cells, Cultured / metabolism
-
Tumor Cells, Cultured / transplantation*
-
Vaccines, Synthetic / administration & dosage
-
Vaccines, Synthetic / adverse effects
-
Vaccines, Synthetic / genetics
-
Vaccines, Synthetic / immunology
Substances
-
Cancer Vaccines
-
Neoplasm Proteins
-
Suppressor Factors, Immunologic
-
Tgfb1 protein, mouse
-
Transforming Growth Factor beta
-
Transforming Growth Factor beta1
-
Vaccines, Synthetic