Lentiviral-mediated Foxp3 RNAi suppresses tumor growth of regulatory T cell-like leukemia in a murine tumor model.
Foxp3, a member of the forkhead transcription factor family, is a master gene that controls the development and function of CD4(+)CD25(+) regulatory T (Treg) cells. It is thought to contribute to pathogenesis of many different tumors, including ovarian carcinoma and pancreatic, breast and pancreatic ductal adenocarcinoma. Selectively depleted Foxp3-expressing cells with anit-CD25 antibodies or vaccination of Foxp3 mRNA-transfected dendritic cells engender protective immunity against tumor. This study targeted silencing Foxp3 gene expression using RNA interference (RNAi) delivered by a lentiviral vector to evaluate the therapeutic role of Foxp3 short-hairpin RNAs (shRNAs) in a murine model of leukemia. RLmale symbol1, a mouse CD4(+)CD25(+) leukemia cell with Foxp3 expression, was used as the leukemia animal model. By infecting RLmale symbol1 cells with Lenti-Foxp3-siRNA, we reduced Foxp3 gene expression and the suppressive function of CD4(+)CD25(-) effector cells stimulated with ConA. Moreover, lentiviral-mediated Foxp3 RNAi transduced into RLmale symbol1 cell or injected into the tumor showed suppressive effects on tumor growth and prolonged the survival of tumor-transplanted mice. However, this suppressive effect was abrogated in NOD-SCID mice transplanted with Lenti-Foxp3-siRNA-infected RLmale symbol1 cells. In conclusion, inhibiting Foxp3 gene expression by shRNAs effectively decreases tumor growth of Treg cell-like leukemia. The results may provide a novel strategy for future immunotherapy against cancers.
Tsai
B-Y
BY
Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
Suen
J-L
JL
Chiang
B-L
BL
D000818:Animals; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors*; D015316:Genetic Therapy; D016086:Lentivirus / Q000235:genetics*; D007942:Leukemia, Experimental / Q000235:genetics / Q000628:therapy*; D015458:Leukemia, T-Cell / Q000235:genetics / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D034622:RNA Interference; D020871:RNA Stability
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse