Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4More about Open Access at the Crick
Authors listJ Chauhan M Grandits LCGF Palhares S Mele M Nakamura J López-Abente S Crescioli R Laddach P Romero-Clavijo A Cheung C Stavraka AM Chenoweth HS Sow G Chiaruttini AE Gilbert T Dodev A Koers G Pellizzari KM Ilieva F Man N Ali C Hobbs S Lombardi DA Lionarons HJ Gould AJ Beavil JLC Geh AD MacKenzie Ross C Healy E Calonje Julian Downward FO Nestle S Tsoka DH Josephs PJ Blower P Karagiannis KE Lacy J Spicer SN Karagiannis HJ Bax
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Outcomes 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.
Journal Nature Communications
Issue number 1