35: Oral rapamycin prevents carcinogen and inflammation-induced skin carcinogenesis through an IFN-γ-dependent mechanism

Abstract

Cancer prevention is a cost-effective alternative to treatment. Oral rapamycin (eRapa) prevents distinct cancers and extends life in mice [1] , making it a candidate broad-spectrum cancer prevention agent. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), has significant immune effects that are unstudied in cancer. We hypothesize that eRapa prevents cancer through improved cancer immune surveillance, which we tested in a carcinogen-induced, inflammation-driven skin cancer model. eRapa was used at 14 ppm microencapsulated rapamycin. Skin cancer. Wild-type C57BL/6 (WT) or syngeneic β δ knockout (KO) and interferon (IFN)- γ KO mice (lacking all T cells or IFN- γ , respectively) got eRapa or control for 1 month, followed once with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), then twice weekly applications with the inflammatory agent 12-O-tetradecanoylphorbol (TPA) for 24 weeks. Flow cytometry assessed cells and IFN- γ . Statistics. Tumors (unpaired t test and 2-way ANOVA) and malignant degeneration (Fischer exact test). eRapa reduced benign ( p = .004) and malignant ( p = .03) tumors in WT mice. T cells and IFN- γ mediate cancer immune surveillance so their effects on eRapa cancer prevention were studied. eRapa reduced skin tumors in β δ KO mice lacking all T cells ( p = .04), but not in IFN- γ KO mice ( p = .13), consistent with loss of beneficial eRapa-induced, non-T cell IFN- γ . In support, WT or IFN- γ KO T cell transfer into IFN- γ KO mice did not alter eRapa cancer prevention in this model. In WT mice on DMBA/TPA, eRapa increased IFN- γ producing dermal natural killer (NK) cells ( p < .0001) that can mediate skin cancer immune surveillance. There was a loss of this eRapa-mediated dermal NK cell increase in IFN- γ KO mice, suggesting that eRapa-mediated IFN- γ facilitated local NK cell accumulation. eRapa prevents carcinogen and inflammation-induced skin cancer, which involves a non-T cell that could be an NK cell, and is IFN- γ dependent. We also show that eRapa prevents cancer and extends life in distinct mouse cancer models, which paves the way for use of mTOR inhibitors as broad spectrum human cancer prevention agents.