Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4
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Published:2023-04-25
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Chauhan Jitesh, Grandits Melanie, Palhares Lais C. G. F., Mele Silvia, Nakamura Mano, López-Abente Jacobo, Crescioli Silvia, Laddach Roman, Romero-Clavijo PabloORCID, Cheung AnthonyORCID, Stavraka CharaORCID, Chenoweth Alicia M., Sow Heng Sheng, Chiaruttini Giulia, Gilbert Amy E., Dodev Tihomir, Koers Alexander, Pellizzari GiuliaORCID, Ilieva Kristina M., Man FrancisORCID, Ali Niwa, Hobbs Carl, Lombardi Sara, Lionarons Daniël A., Gould Hannah J.ORCID, Beavil Andrew J.ORCID, Geh Jenny L. C.ORCID, MacKenzie Ross Alastair D.ORCID, Healy Ciaran, Calonje Eduardo, Downward JulianORCID, Nestle Frank O., Tsoka Sophia, Josephs Debra H., Blower Philip J., Karagiannis Panagiotis, Lacy Katie E., Spicer JamesORCID, Karagiannis Sophia N.ORCID, Bax Heather J.ORCID
Abstract
AbstractOutcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.
Funder
DH | National Institute for Health Research Cancer Research UK Department of Health | National Health and Medical Research Council Guy's and St Thomas' Charity Breast Cancer Now Innovate UK Rotary Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference73 articles.
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