title: TGF-beta insensitive dendritic cells: an efficient vaccine for murine prostate cancer.
abstract: Dendritic cells (DCs) are highly potent initiators of the immune response, but DC effector functions are often inhibited by immunosuppressants such as transforming growth factor beta (TGF-beta). The present study was conducted to develop a treatment strategy for prostate cancer using a TGF-beta-insensitive DC vaccine. Tumor lysate-pulsed DCs were rendered TGF-beta insensitive by dominant-negative TGF-beta type II receptor (TbetaRIIDN), leading to the blockade of TGF-beta signals to members of the Smad family, which are the principal cytoplasmic intermediates involved in the transduction of signals from TGF-beta receptors to the nucleus. Expression of TbetaRIIDN did not affect the phenotype of transduced DCs. Phosphorylated Smad-2 was undetectable and expression of surface co-stimulatory molecules (CD80/CD86) were upregulated in TbetaRIIDN DCs after antigen and TGF-beta1 stimulation. Vaccination of C57BL/6 tumor-bearing mice with the TbetaRIIDN DC vaccine induced potent tumor-specific cytotoxic T lymphocyte responses against TRAMP-C2 tumors, increased serum IFN-gamma and IL-12 level, inhibited tumor growth and increased mouse survival. Furthermore, complete tumor regression occurred in two vaccinated mice. These results demonstrate that blocking TGF-beta signals in DC enhances the efficacy of DC-based vaccines.
authors.affiliation: Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Fu-Li
authors.initials: FL
authors.lastname: Wang
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Qin
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Wen
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.forename: Wei-de
authors.initials: WD
authors.lastname: Zhong
authors.forename: Ying-Lu
authors.initials: YL
authors.lastname: Guo
authors.forename: He
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II