Rapamycin prevents tobacco-carcinogen induced lung tumorigenesis and selectively reduces lung-associated Foxp3 positive cells

B8

Inhibitors of the serine/threonine kinase mTOR can prevent tumorigenesis in many model systems, but the use of mTOR inhibitors for cancer prevention in humans is theoretically limited by the risk of secondary malignancies, which was observed in patients receiving rapamycin as part of multi-drug immunosuppressive therapy. However, little is known about immune modulation by rapamycin as a single agent. Previously, we showed that physiologic concentrations of rapamycin inhibited lung tumorigenesis driven by a tobacco-specific carcinogen, NNK. Here we characterize immune modulation in this system. NNK alone acutely depleted multiple lineages of immune splenic cells without suppressing immune function. In contrast to these nominal systemic effects, NNK doubled the percentage of cells expressing the Treg marker Foxp3 in lung tissues prior to tumor development and caused a dose-dependent increase in tumor-infiltrating Foxp3+ cells at 12 weeks. NNK administration did not increase the overall number of CD3+ cells, suggesting that the effect of NNK was specific for Foxp3+ cells. Rapamycin rapidly decreased splenic Foxp3+/CD4+ cells, and was associated with depletion of Foxp3+ cells in lung tissues. At 12 wk, rapamycin inhibited tumorigenesis, decreased the number of tumor-associated Foxp3+ cells by 88%, modestly decreased systemic CD4+ and CD8+ cells, and did not induce an immunosuppressive Th2 phenotype. Thus, single-agent rapamycin prevents lung infiltration of Foxp3+ cells that occurs early in tumorigenesis without causing profound immunosuppression.