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Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors.
Cancer Res. 2012 Feb 01; 72(3):581-91.CR

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+Show Affiliations

Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22158905

Citation

Marshall, Neil A., et al. "Immunotherapy With PI3K Inhibitor and Toll-like Receptor Agonist Induces IFN-γ+IL-17+ Polyfunctional T Cells That Mediate Rejection of Murine Tumors." Cancer Research, vol. 72, no. 3, 2012, pp. 581-91.
Marshall NA, Galvin KC, Corcoran AM, et al. Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res. 2012;72(3):581-91.
Marshall, N. A., Galvin, K. C., Corcoran, A. M., Boon, L., Higgs, R., & Mills, K. H. (2012). Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Research, 72(3), 581-91. https://doi.org/10.1158/0008-5472.CAN-11-0307
Marshall NA, et al. Immunotherapy With PI3K Inhibitor and Toll-like Receptor Agonist Induces IFN-γ+IL-17+ Polyfunctional T Cells That Mediate Rejection of Murine Tumors. Cancer Res. 2012 Feb 1;72(3):581-91. PubMed PMID: 22158905.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors. AU - Marshall,Neil A, AU - Galvin,Karen C, AU - Corcoran,Anna-Maria B, AU - Boon,Louis, AU - Higgs,Rowan, AU - Mills,Kingston H G, Y1 - 2011/12/09/ PY - 2011/12/14/entrez PY - 2011/12/14/pubmed PY - 2012/3/31/medline SP - 581 EP - 91 JF - Cancer research JO - Cancer Res. VL - 72 IS - 3 N2 - 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. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/22158905/Immunotherapy_with_PI3K_inhibitor_and_Toll_like_receptor_agonist_induces_IFN_γ+IL_17+_polyfunctional_T_cells_that_mediate_rejection_of_murine_tumors_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22158905 DB - PRIME DP - Unbound Medicine ER -