Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4.

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.

• Authors: Jitesh Chauhan, Melanie Grandits, Lais C G F Palhares, Silvia Mele, Mano Nakamura, Jacobo López-Abente, Silvia Crescioli, Roman Laddach, Pablo Romero-Clavijo, Anthony Cheung, Chara Stavraka, Alicia M Chenoweth, Heng Sheng Sow, Giulia Chiaruttini, Amy E Gilbert, Tihomir Dodev, Alexander Koers, Giulia Pellizzari, Kristina M Ilieva, Francis Man, Niwa Ali, Carl Hobbs, Sara Lombardi, Daniël A Lionarons, Hannah J Gould, Andrew J Beavil, Jenny L C Geh, Alastair D MacKenzie Ross, Ciaran Healy, Eduardo Calonje, Julian Downward, Frank O Nestle, Sophia Tsoka, Debra H Josephs, Philip J Blower, Panagiotis Karagiannis, Katie E Lacy, James Spicer, Sophia N Karagiannis, Heather J Bax
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 2192 (04 25 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 37185332 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• chondroitin sulfate proteoglycan 4
• Proteoglycans
• Antigens
• Chondroitin Sulfate Proteoglycans
• Antibodies, Monoclonal
• Immunoglobulin E

Topics

• Humans
• Mice
• Animals
• Proteoglycans (metabolism)
• Antigens
• Chondroitin Sulfate Proteoglycans
• Melanoma (metabolism)
• Antibodies, Monoclonal (pharmacology)
• Immunoglobulin E
• Tumor Microenvironment