Targeting AKT Signaling Sensitizes Cancer to Cellular Immunotherapy

摘要: The promise of cancer immunotherapy is long-term disease control with high specificity and low toxicity. However, many cancers fail immune interventions, secretion immunosuppressive factors, defective antigen presentation, expression death ligands or serpins are regarded as main escape mechanisms. Here, we study whether deregulation growth survival factor signaling, which encountered in most human cancers, provides another level protection against immunologic tumor eradication. We show two models that activated cell autonomous protein kinase B (PKB)/AKT signaling mediates resistance suppression by antigen-specific CTLs vitro adoptively transferred cellular effectors vivo. PKB/AKT-dependent immunoresistance established tumors reversed genetic endogenous Mcl-1, an antiapoptotic member the Bcl-2 family. Mechanistically, deregulated PKB/AKT stabilizes Mcl-1 a mammalian target rapamycin (mTOR)–dependent pathway. Treatment mTOR inhibitor effectively sensitizes to adoptive In conclusion, cell–intrinsic regulates susceptibility immune-mediated cytotoxicity. Combined targeting signal transduction pathways may be critical for improvement immunotherapies. [Cancer Res 2008;68(10):3899–906]