title: Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors.
abstract: The immunosuppressive microenvironment in tumors hampers the induction of antitumor immunity by vaccines or immunotherapies. Toll-like receptor (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 phosphoinositide 3-kinase (PI3K) relieve immunosuppression to heighten the proinflammatory effects of TLR ligands that support antitumor immunity. Multiple strategies to inhibit PI3K in dendritic cells (DC) each led to suppression of interleukin (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 antitumor properties of TLR ligands, eliciting tumor regression directly but also indirectly by relieving suppressive signals that restrict potent antitumor T-cell responses. These findings suggest important uses for PI3K inhibitors in heightening responses to cancer immunotherapy and immunochemotherapy.
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Marshall
authors.forename: Karen C
authors.initials: KC
authors.lastname: Galvin
authors.forename: Anna-Maria B
authors.initials: AM
authors.lastname: Corcoran
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Rowan
authors.initials: R
authors.lastname: Higgs
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005408:Flagellin / Q000008:administration & dosage; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D045162:Thiazolidinediones / Q000008:administration & dosage; D051198:Toll-Like Receptor 5 / Q000819:agonists* / Q000378:metabolism; D014227:Triazines / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D004791:Enzyme Inhibitors; D005408:Flagellin; D007371:Interferon-gamma; D020381:Interleukin-17; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D045162:Thiazolidinediones; D051198:Toll-Like Receptor 5; D014227:Triazines; C512438:5-(5-(4-fluoro-2-hydroxyphenyl)furan-2-ylmethylene)thiazolidine-2,4-dione; C510150:ZSTK474