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Reduces the Efficacy of Dendritic Cell/Tumor Fusion Vaccine1
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109
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-
, which may hamper host immune response to DC vaccine. In this study, we demonstrated that TGF- produced by tumors significantly reduced the potency of DC/tumor fusion vaccines. TGF--secreting (CT26-TGF-) stable mouse colon cancer cell lines were generated using a retroviral vector expressing TGF-. A non-TGF--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- fusion cells failed to induce a strong T cell proliferative response in vitro, mainly due to the effect of TGF- on T cell responsiveness rather than DC stimulatory capability. Animals vaccinated with DC/CT26-TGF- 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- did not appear to lessen the efficacy of DC vaccine. These data suggest that tumor-derived TGF- reduces the efficacy of DC/tumor fusion vaccine via an in vivo mechanism. Neutralization of TGF- produced by the fusion cells may enhance the effectiveness of DC-based immunotherapy.
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