Immunization with TGF-beta antisense oligonucleotide-modified autologous tumor vaccine enhances the antitumor immunity of MBT-2 tumor-bearing mice through upregulation of MHC class I and Fas expressions.
The major purpose of this study was to define if the immunosuppressive effect of a transforming growth factor-beta (TGF-beta)-producing autologous tumor vaccine can be abrogated and rendered immunogenic by suppressing its TGF-beta secretion with antisense strategy. In this study, using a TGF-beta antisense gene modified MBT-2 tumor cell line [MBT-2/TGF-beta(-)#3] which we established by ourselves, we first demonstrated that the amounts of TGF-beta produced by irradiated (IR) and non-irradiated MBT-2/TGF-beta(-) #3 were both significantly decreased when detected after in vitro culture for 48 hours. The result of flow cytometry analysis reveals that decreased production of TGF-beta led to the increased expressions of MHC class I molecule and Fas on the surface of MBT-2 tumor cells. This finding may in part explain why the splenocytes obtained from day 17 tumor bearing mice (D17TBM) immunized with IRMBT-2/TGF-beta(-)#3 on day 26 expressed a higher in vitro cytotoxic activity against MBT-2 tumor cells and hence ensured a better survival of D17TBM when they were rechallenged with a two-fold higher amount of wild-type MBT-2 tumor cells, 48 hours after surgical removal of the primary tumor. Our result implies that decreasing the amount of TGF-beta secreted from the autologous tumor vaccine by antisense strategy may significantly improve its immunogenicity through up-regulation of both MHC class I and Fas expressions. Therefore, this could provide an alternative approach for future active immunotherapy.
Tzai
T S
TS
Department of Urology, Medical College, National Cheng Kung University, Tainan, Taiwan.
Shiau
A L
AL
Liu
L L
LL
Wu
C L
CL
D000818:Animals; D019496:Cancer Vaccines; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D007114:Immunization; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis*
D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D016376:Oligonucleotides, Antisense; D016212:Transforming Growth Factor beta; D019014:fas Receptor