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. RL1, a mouse CD4+ CD25+ leukemia cell with Foxp3 expression, was used as the leukemia animal model. By infecting RL1 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 RL1 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 RL1 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. ? 2010 Macmillan Publishers Limited All rights reserved.