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Cancer Res. 2017 Mar 1;77(5):1127-1141. doi: 10.1158/0008-5472.CAN-16-1829. Epub 2017 Jan 17.

Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling.

Author information

1
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.
2
NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, London, United Kingdom.
3
Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
4
Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
5
Division of Asthma, Allergy and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.
6
Tumor Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
7
Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
8
King's Health Partners Cancer Biobank, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
9
Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom.
10
Biotherapeutics Development Unit, Cancer Research UK, South Mimms, Hertfordshire, United Kingdom.
11
Centre for Drug Development, Cancer Research UK, London, United Kingdom.
12
Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, London, United Kingdom.
13
Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione, IRCCS Istituto Nazionale dei Tumori Milano, Milan, Italy.
14
Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
15
Sequani, Ledbury, Herefordshire, United Kingdom.
16
Institut National de la Santé et de la Recherche Médicale U1011, Lille, France.
17
Immunology and Inflammation Therapeutic Research Area, Sanofi US, Cambridge, Massachusetts.
18
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.

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 and in vivo proof 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.

PMID:
28096174
PMCID:
PMC6173310
DOI:
10.1158/0008-5472.CAN-16-1829
[Indexed for MEDLINE]
Free PMC Article

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