title: A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis.
abstract: BACKGROUND
  K-Ras mutations are characteristic of human lung adenocarcinomas and occur almost exclusively in smokers. In preclinical models, K-Ras mutations are necessary for tobacco carcinogen-driven lung tumorigenesis and are sufficient to cause lung adenocarcinomas in transgenic mice. Because these mutations confer resistance to commonly used cytotoxic chemotherapies and targeted agents, effective therapies that target K-Ras are needed. Inhibitors of mTOR such as rapamycin can prevent K-Ras-driven lung tumorigenesis and alter the proportion of cytotoxic and Foxp3+ regulatory T cells, suggesting that lung-associated T cells might be important for tumorigenesis.
  
  
  METHODS
  Lung tumorigenesis was studied in three murine models that depend on mutant K-Ras; a tobacco carcinogen-driven model, a syngeneic inoculation model, and a transgenic model. Splenic and lung-associated T cells were studied using flow cytometry and immunohistochemistry. Foxp3+ cells were depleted using rapamycin, an antibody, or genetic ablation.
  
  
  RESULTS
  Exposure of A/J mice to a tobacco carcinogen tripled lung-associated Foxp3+ cells prior to tumor development. At clinically relevant concentrations, rapamycin prevented this induction and reduced lung tumors by 90%. In A/J mice inoculated with lung adenocarcinoma cells resistant to rapamycin, antibody-mediated depletion of Foxp3+ cells reduced lung tumorigenesis by 80%. Likewise, mutant K-Ras transgenic mice lacking Foxp3+ cells developed 75% fewer lung tumors than littermates with Foxp3+ cells.
  
  
  CONCLUSIONS
  Foxp3+ regulatory T cells are required for K-Ras-mediated lung tumorigenesis in mice. These studies support clinical testing of rapamycin or other agents that target Treg in K-Ras driven human lung cancer.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Granville
authors.forename: Regan M
authors.initials: RM
authors.lastname: Memmott
authors.forename: Andria
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authors.lastname: Balogh
authors.forename: Jacopo
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authors.lastname: Mariotti
authors.forename: Shigeru
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authors.lastname: Kawabata
authors.forename: Wei
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authors.lastname: Han
authors.forename: Jaclyn
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authors.lastname: Lopiccolo
authors.forename: Jason
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authors.lastname: Foley
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
authors.forename: M Christine
authors.initials: MC
authors.lastname: Hollander
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis