title: Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling.
abstract: IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibody-dependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen-specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined andin vivoproof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcε receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FRα), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRα. Compared with IgG, anti-FRα IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNFα+and CD80+macrophages plus elevated TNFα and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNFα and MCP-1 correlated with IgE-mediated tumor cytotoxicity by human monocytes and with longer patient survival in clinical specimens of ovarian cancer. Monocytes responded to IgE but not IgG exposure by upregulating TNFα, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNFα receptor signaling abrogated induction of MCP-1, implicating it in the antitumor effects of IgE. Overall, these findings show how antitumor IgE reprograms monocytes and macrophages in the tumor microenvironment, encouraging the clinical use of IgE antibody technology to attack cancer beyond the present exclusive reliance on IgG.Cancer Res; 77(5); 1127-41. ©2017 AACR.
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.
authors.forename: Debra H
authors.initials: DH
authors.lastname: Josephs
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.|Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Bax
authors.affiliation: NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.|Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.|Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Dodev
authors.affiliation: Tumor Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors.forename: Mirella
authors.initials: M
authors.lastname: Georgouli
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Mano
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pellizzari
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.|Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Saul
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Karagiannis
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cheung
authors.affiliation: Tumor Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Herraiz
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.|Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Ilieva
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.
authors.forename: Isabel
authors.initials: I
authors.lastname: Correa
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.|Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Fittall
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Crescioli
authors.affiliation: King's Health Partners Cancer Biobank, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Gazinska
authors.affiliation: King's Health Partners Cancer Biobank, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Natalie
authors.initials: N
authors.lastname: Woodman
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Mele
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Giulia
authors.initials: G
authors.lastname: Chiaruttini
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Gilbert
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koers
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors.forename: Marguerite
authors.initials: M
authors.lastname: Bracher
authors.affiliation: Biotherapeutics Development Unit, Cancer Research UK, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Selkirk
authors.affiliation: Biotherapeutics Development Unit, Cancer Research UK, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Heike
authors.initials: H
authors.lastname: Lentfer
authors.affiliation: Centre for Drug Development, Cancer Research UK, London, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Barton
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Elliott
authors.initials: E
authors.lastname: Lever
authors.affiliation: Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, London, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Muirhead
authors.affiliation: Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, London, United Kingdom.
authors.forename: Sophia
authors.initials: S
authors.lastname: Tsoka
authors.affiliation: Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione, IRCCS Istituto Nazionale dei Tumori Milano, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.affiliation: Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione, IRCCS Istituto Nazionale dei Tumori Milano, Milan, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Figini
authors.affiliation: Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Montes
authors.affiliation: Sequani, Ledbury, Herefordshire, United Kingdom.
authors.forename: Noel
authors.initials: N
authors.lastname: Downes
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1011, Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Dombrowicz
authors.affiliation: Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Corrigan
authors.affiliation: NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.|Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.|Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Beavil
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.|Immunology and Inflammation Therapeutic Research Area, Sanofi US, Cambridge, Massachusetts.
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.affiliation: Centre for Drug Development, Cancer Research UK, London, United Kingdom.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Jones
authors.affiliation: NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.|Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.|Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Gould
authors.affiliation: Tumor Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sanz-Moreno
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Blower
authors.affiliation: Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: James F
authors.initials: JF
authors.lastname: Spicer
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom. sophia.karagiannis@kcl.ac.uk.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.|Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Sophia N
authors.initials: SN
authors.lastname: Karagiannis
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D058975:Folate Receptor 1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D058975:Folate Receptor 1; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C026408:anti-IgE antibodies