Cancer Res.：发现治疗癌症的新疫苗

Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T-cells that mediate rejection of murine tumors

Neil A Marshall, Karen C Galvin, Anna-Maria B Corcoran, Louis Boon, Rowan Higgs, and Kingston H.G. Mills

Abstract： The immunosuppressive microenvironment in tumors hampers the induction of anti-tumor immunity by vaccines or immunotherapies. TLR ligands have the potential to treat tumors, but they can exert a mixture of positive and negative effects on inflammation in the tumor microenvironment. In this study we show that specific small molecule inhibitors of PI3K relieve immunosuppression to heighten the pro-inflammatory effects of TLR ligands that support anti-tumor immunity. Multiple strategies to inhibit PI3K in dendritic cells (DC) each led to suppression of IL-10 and TGF-β but did affect IL-12 or IL-1β induction by the TLR5 ligand flagellin. In three different mouse models of cancer, combining flagellin with a class-I PI3K inhibitor, either with or without a DC vaccine, delayed tumor growth and increased survival, with some animals exhibiting complete rejection and resistance to secondary challenge. Tumor growth suppression was associated with increased accumulation of polyfunctional T cells that secreted multiple effector cytokines, including IFN-γ, IL-17 and IL-2. Therapeutic protection was abolished in mice deficient in IL-17 or deprived of IFN-γ. Together, our results indicate that PI3K inhibition heighten the anti-tumor properties of TLR ligands, eliciting tumor regression directly but also indirectly by relieving suppressive signals that restrict potent anti-tumor T cell responses. These findings suggest important uses for PI3K inhibitors in heightening responses to cancer immunotherapy and immunochemotherapy. Received January 26, 2011. Revision received November 17, 2011. Accepted November 29, 2011.