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

Courtney A. Granville, Regan M. Memmott, Andria Balogh, Jacopo Mariotti, Shigeru Kawabata, Wei Han, Jaclyn LoPiccolo, Jason Foley, David J. Liewehr, Seth M. Steinberg, Daniel H. Fowler, M. Christine Hollander, Phillip A. Dennis

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere5061
JournalPloS one
Volume4
Issue number3
DOIs
StatePublished - Mar 30 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Granville, C. A., Memmott, R. M., Balogh, A., Mariotti, J., Kawabata, S., Han, W., LoPiccolo, J., Foley, J., Liewehr, D. J., Steinberg, S. M., Fowler, D. H., Hollander, M. C., & Dennis, P. A. (2009). A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PloS one, 4(3), [e5061]. https://doi.org/10.1371/journal.pone.0005061