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

PLoS One. 2009;4(3):e5061. doi: 10.1371/journal.pone.0005061. Epub 2009 Mar 30.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Forkhead Transcription Factors
  • Genes, ras / genetics*
  • Lung Neoplasms / etiology*
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Sirolimus / pharmacology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / pathology*
  • Tobacco

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Sirolimus