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Targeting AKT Signaling Sensitizes Cancer to Cellular Immunotherapy

¹ Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen, Germany; ² Department of Medicine III, Johannes Gutenberg University, Mainz, Germany; and ³ Department of Hematology and Van Creveld Clinic, University Medical Center Utrecht, Utrecht, the Netherlands

Requests for reprints: Martin Schuler, Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany. Phone: 49-201-723-2000; Fax: 49-201-723-5924; E-mail: martin.schuler{at}uk-essen.de.

Key Words: PKB/AKT • immunotherapy • immunoresistance • apoptosis • CTL

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 immunologic tumor eradication. We show in two models that activated cell autonomous protein kinase B (PKB)/AKT signaling mediates resistance against tumor suppression by antigen-specific CTLs 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 antiapoptotic member of the Bcl-2 family. Mechanistically, deregulated PKB/AKT stabilizes Mcl-1 expression in a mammalian target of rapamycin (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. [Cancer Res 2008;68(10):3899–906]