Targeting AKT signaling sensitizes cancer to cellular immunotherapy
In: Cancer Research, Jg. 68 (2008), S. 3899-3906
Zeitschriftenaufsatz / Fach: Medizin
The promise of cancer immunotherapy is long-term disease control with high specificity and low toxicity. However, many cancers fail immune interventions, and secretion of immunosuppressive factors, defective antigen presentation and expression of death ligands or serpins are regarded as main escape mechanisms. Here we study, whether deregulation of growth and survival factor signaling, which is encountered in most human cancers, provides another level of protection against immunological tumor eradication. We demonstrate in two models that activated cell-autonomous protein kinase B (PKB)/AKT signaling mediates resistance against tumor suppression by antigen-specific cytotoxic T lymphocytes (CTL) in vitro and adoptively transferred cellular immune effectors in vivo. PKB/AKT-dependent “immunoresistance” of established tumors is reversed by genetic suppression of endogenous Mcl-1, an anti-apoptotic member of the Bcl-2 family. Mechanistically, deregulated PKB/AKT stabilizes Mcl-1 expression in an mTOR-dependent pathway. Treatment with the mTOR inhibitor rapamycin effectively sensitizes established cancers to adoptive immunotherapy in vivo. In conclusion, cancer cell-intrinsic PKB/AKT signaling regulates the susceptibility to immune-mediated cytotoxicity. Combined targeting of signal transduction pathways may be critical for improvement of cancer immunotherapies.