Oral rapamycin (eRapa) requires IFN-γ and promotes γδ T cell cytotoxicity to prevent carcinogen and inflammation-induced dermal cancer (TUM9P.1003)

Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, prevents distinct cancers in mice and prolongs life, making it a candidate cancer prevention (and life extension) agent. We hypothesized that eRapa cancer prevention includes immune effects, as mTOR is pivotal in immunity. We tested immune effects in carcinogen (DMBA) and inflammation (TPA)-induced dermal carcinogenesis with eRapa daily at 14 ppm, which protected 100% from skin cancer in wild type (WT) mice. Tumor mTORC1 was not suppressed, supporting eRapa immune effects. γδ T cells and IFN-γ are protective in this model. In δ TCR KO (no γδ T cells) and IFN-γ KO mice, eRapa cancer protection was lost, confirming immune mechanisms. IFN-γ KO mice had significantly reduced CD69 + Lamp1 + GzB + CXCR3 + epidermal γδ T cells and CXCL10, suggesting IFN-γ is required for epidermal γδ T cell migration (via CXCR3/CXCL10), activation and cytolysis. Bone marrow (BM) chimeras showed eRapa skin cancer protection and maximum γδ T cell epidermal infiltration requires IFN-γ signals in BM ( e.g., γδ T cells) and non-BM ( e.g., epidermal) cells. Intratumor injections of WT but not Prf1 (perforin) KO γδ T cells regressed DMBA/TPA tumors in δ TCR KO mice on eRapa but not control, showing eRapa boosts anti-tumor γδ T cell cytotoxicity. Our data confirm eRapa cancer prevention through immune mechanisms, challenging the paradigm of mTOR effects solely on cancer cells for prevention, and suggesting novel immune-mediated life extension mechanisms.