Anti-folate receptor-α IgE but not IgG recruits macrophages to attack tumors via TNFa/MCP-1 signaling

Debra H. Josephs, Heather J. Bax, Tihomir Dodev, Mirella Georgouli, Mano Nakamura, Giulia Pellizzari, Louise Saul, Panagiotis Karagiannis, Anthony Cheung, Cecilia Herraiz, Kristina M. Ilieva, Isabel Correa, Matthew Fittall, Silvia Crescioli, Patrycja Gazinska, Natalie Woodman, Silvia Mele, Giulia Chiaruttini, Amy E. Gilbert, Alexander KoersMarguerite Bracher, Christopher Selkirk, Heike Lentfer, Claire Barton, Elliott Lever, Gareth Muirhead, Sophia Tsoka, Silvana Canevari, Mariangela Figini, Ana Montes, Noel Downes, David Dombrowicz, Christopher J. Corrigan, Andrew J. Beavil, Frank O. Nestle, Paul S. Jones, Hannah J. Gould, Victoria Sanz-Moreno, Philip J. Blower, James F. Spicer, Sophia N. Karagiannis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)
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IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibodydependent 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-Fce 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.

Original languageEnglish
Pages (from-to)1127-1141
Number of pages15
JournalCancer Research
Issue number5
Early online date17 Jan 2017
Publication statusPublished - 31 Mar 2017


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