Abstract
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.
Original language | English |
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Pages (from-to) | 2192 |
Journal | Nature Communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
Publication status | Published - 25 Apr 2023 |
Keywords
- Humans
- Mice
- Animals
- Proteoglycans/metabolism
- Antigens
- Chondroitin Sulfate Proteoglycans
- Melanoma/metabolism
- Antibodies, Monoclonal/pharmacology
- Immunoglobulin E
- Tumor Microenvironment