Abstract PL01-04: The role of regulatory T cells in K-Ras driven lung cancer Free

K-Ras mutations occur in up to 30% of human lung adenocarcinomas (Salgia and Skarin 1998) and occur almost exclusively in patients with a history of smoking. These mutations confer resistance to commonly used cytotoxic chemotherapies as well as targeted agents (Eberhard, Johnson et al. 2005). In preclinical mouse models of lung cancer, K-Ras mutations are necessary for tobacco carcinogen-driven lung tumorigenesis and are sufficient to cause lung adenocarcinomas in transgenic mice (Johnson, Mercer et al. 2001). Inflammation is characteristic of smoking-related lung cancer and preclinical models of K-Ras-driven lung tumorigenesis. Specific components of the inflammatory response such as regulatory T cells (Treg) regulate inflammation and are thought to contribute to tumorigenesis. Because inhibitors of mTOR such as the immunosuppressant rapamycin can prevent K-Ras mediated murine lung tumorigenesis (Wislez, Spencer et al. 2005; Granville, Warfel et al. 2007), we hypothesized that the anti-tumor effects of rapamycin might be related to alterations in lung-associated inflammation.

Lung tumorigenesis was studied in three different 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. Exposure of A/J mice to the tobacco-carcinogen NNK that causes K-Ras mutations (Belinsky, Devereux et al. 1989) tripled the fraction of lung-associated Treg prior to tumor development. Induction of lung tumors and induction of lung associated Foxp3+ cells by NNK was dose dependent. When administered to achieve trough levels comparable to that in humans, rapamycin prevented the induction of lung associated Foxp3+ cells by NNK, coincident with a 90% decrease in lung tumors. In A/J mice inoculated with syngeneic lung adenocarcinoma cells that were resistant to the anti-proliferative effects of rapamycin, rapamycin neither inhibited tumor growth nor decreased Treg. In contrast, depletion of Treg in inoculated mice using an anti-CD25 antibody prevented lung tumorigenesis by 80%. Transgenic mice that express mutant K-Ras (K-RasLA2) also develop lung tumors with infiltrating Foxp3+ cells, and when K-RasLA2 mice were crossed to genetically engineered mice that bear a loss of function mutation in Foxp3, lung tumorigenesis was inhibited by 75%.

These studies show that Treg are required for K-Ras-mediated lung tumorigenesis, and provide a strong rationale to clinically evaluate rapamycin or other agents that decrease Treg, to determine if decreasing Treg will inhibit K-Ras driven lung cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PL01-04.