Microencapulated rapamycin prevents carcinogen and inflammation driven colon cancer through immune mechanisms

Abstract

Abstract We tested microencapsulated rapamycin (eRapa, ~2.2 mg/kg rapamycin/mouse/day) in carcinogen (azoxymethane, AOM) + inflammatory agent (dextran sodium sulfate, DSS) colon cancer. WT BL6 mice fed eRapa before, and during AOM/DSS had significantly fewer colon tumors and tumor burden than control fed mice (empty microcapsules). eRapa prevented colon cancer in δ TCR KO mice lacking γδ T cells but not in IFN-γ KO mice. In carcinogen (DMBA) + inflammatory agent (TPA) skin cancer, IFN-γ and γδ T cells were both needed for eRapa cancer prevention, showing tumor-specific and common immune requirements for eRapa-mediated cancer prevention. In βδ TCR KO mice lacking all T cells, AOM/DSS induced no cancer or only few tumors, suggesting αβ T cells are required for colon neoplasia and cancer in the AOM/DSS model. Protection from acute colitis in this model usually predicts colon cancer protection. Strikingly, however, eRapa did not prevent acute clinical or histologic colitis induced by DSS, despite cancer protection, suggesting effects on chronic colitis, or induction of cancer-protective but not acute colitis-protective mechanisms. In acute colitis, eRapa significantly decreased spleen and colon weights and CD3+CD4+ T cells, and increased mesenteric lymph node γδ T cells (with decreased Vγ1.1+ and increased Vγ2+ subsets) consistent with altered inflammation and reduced CD4-CXCR3+ and CD4-α4β7 T cells (likely γδ T cells) consistent with altered trafficking but did not affect CCR9+ T cells. In chronic colitis, eRapa significantly increased γδ T cells (with no changes in Vγ1.1+ or Vγ2+ subsets) that could mediate cancer protection. These novel immune effects of rapamycin help define its cancer prevention mechanisms and define novel clinical uses.