| Autor: |
Sophia N. Karagiannis, James F. Spicer, Philip J. Blower, Victoria Sanz-Moreno, Hannah J. Gould, Paul S. Jones, Frank O. Nestle, Andrew J. Beavil, Christopher J. Corrigan, David Dombrowicz, Noel Downes, Ana Montes, Mariangela Figini, Silvana Canevari, Sophia Tsoka, Gareth Muirhead, Elliott Lever, Claire Barton, Heike Lentfer, Christopher Selkirk, Marguerite Bracher, Alexander Koers, Amy E. Gilbert, Giulia Chiaruttini, Silvia Mele, Natalie Woodman, Patrycja Gazinska, Silvia Crescioli, Matthew Fittall, Isabel Correa, Kristina M. Ilieva, Cecilia Herraiz, Anthony Cheung, Panagiotis Karagiannis, Louise Saul, Giulia Pellizzari, Mano Nakamura, Mirella Georgouli, Tihomir Dodev, Heather J. Bax, Debra H. Josephs |
| Rok vydání: |
2023 |
| DOI: |
10.1158/0008-5472.c.6509447.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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