title: Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer.
abstract: Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8(+) cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London WC1E 6DD, UK.
authors.forename: Khaled
authors.initials: K
authors.lastname: Ali
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Dalya R
authors.initials: DR
authors.lastname: Soond
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London WC1E 6DD, UK.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pineiro
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hagemann
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London WC1E 6DD, UK.
authors.forename: Wayne
authors.initials: W
authors.lastname: Pearce
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Ee Lyn
authors.initials: EL
authors.lastname: Lim
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Hicham
authors.initials: H
authors.lastname: Bouabe
authors.affiliation: Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, Hatfield, Hertfordshire AL9 7TA, UK.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Scudamore
authors.affiliation: Piramed Pharma, 957 Buckingham Avenue, Slough, Berkshire, SL1 4NL, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hancox
authors.affiliation: Cancer Signaling and Translational Oncology, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Maecker
authors.affiliation: Cancer Signaling and Translational Oncology, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Friedman
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Turner
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London WC1E 6DD, UK.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases