A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Granville, CA; Memmott, RM; Balogh, A; Mariotti, J; Kawabata, S; Han, W; Lopiccolo, J; Foley, J; Liewehr, DJ; Steinberg, SM; Fowler, DH; Hollander, MC; Dennis, PA

Published Date

  • 2009

Published In

Volume / Issue

  • 4 / 3

Start / End Page

  • e5061 -

PubMed ID

  • 19330036

Pubmed Central ID

  • PMC2659439

Electronic International Standard Serial Number (EISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0005061

Language

  • eng

Conference Location

  • United States