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.
Subject(s)
Cancer Vaccines/adverse effects , Dendritic Cells/transplantation , Neoplasm Proteins/adverse effects , Neoplasms, Experimental/immunology , Neoplasms, Experimental/prevention & control , Suppressor Factors, Immunologic/adverse effects , Transforming Growth Factor beta/adverse effects , Tumor Cells, Cultured/transplantation , Animals , Cancer Vaccines/administration & dosage , Cancer Vaccines/genetics , Cancer Vaccines/immunology , Cell Fractionation , Cell-Free System/immunology , Cell-Free System/metabolism , Coculture Techniques , Cytotoxicity, Immunologic/genetics , Dendritic Cells/immunology , Female , Injections, Intraperitoneal , Lymphocyte Activation/genetics , Mice , Mice, Inbred BALB C , Neoplasm Proteins/blood , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/mortality , 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/blood , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1 , Tumor Cells, Cultured/immunology , Tumor Cells, Cultured/metabolism , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/adverse effects , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunologyABSTRACT
El efecto deletéreo que ocasiona la radioterapia en los diversos aparatos y sistemas del organismo es el factor clave que debe tomarse en consideración para establecer el estado anestésico en el paciente canceroso que necesita ser intervenido quirúrgicamente. Se resume el método terapéutico para realizar procedimiento de braquiterapia y para los enfermos que han sido tratados con anterioridad con quimioterapia y teleterapia. Los pacientes con cáncer tratados con quimioterapia, radiaciones y branquiterapia a menudo ameritan ser intervenidos quirúrgicamente bajo anestesia general o de conducción. Para establecer el estado anestésico deben de tenerse en cuenta los cambios hemodinámicos que ocasiona el propio tumor, así como la radioterapia y los procedimientos quirúrgicos anestésicos prescritos con anterioridad; los padecimientos concomitantes y los medicamentos recetados para su control; las condiciones generales de los individuos que siempre están deterioradas en forma importante; la necesidad de manipular las estructuras anatómicas ampliamente irrigadas y la dificultad para la intubación traqueal, ya sea porque la enfermedad involucra la cabeza y el cuello, o por la rigidez y el edema de la laringe, o por la dificultad para extender el cuello por radiaciones con antelación o por anquilosis temporomaxilar permanente
