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Lentiviral-mediated Foxp3 RNAi suppresses tumor growth of regulatory T cell-like leukemia in a murine tumor model

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Abstract

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. RL♂1, a mouse CD4+CD25+ leukemia cell with Foxp3 expression, was used as the leukemia animal model. By infecting RL♂1 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 RL♂1 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 RL♂1 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.

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Authors and Affiliations

  1. Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China

    B-Y Tsai & B-L Chiang

  2. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    J-L Suen

  3. Department of Microbiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China

    J-L Suen

  4. Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China

    B-L Chiang

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  1. B-Y Tsai
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Tsai, BY., Suen, JL. & Chiang, BL. Lentiviral-mediated Foxp3 RNAi suppresses tumor growth of regulatory T cell-like leukemia in a murine tumor model. Gene Ther 17, 972–979 (2010). https://doi.org/10.1038/gt.2010.38

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