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

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 () and Heather J. Bax ()
Additional contact information
Jitesh Chauhan: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Melanie Grandits: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Lais C. G. F. Palhares: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Silvia Mele: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Mano Nakamura: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Jacobo López-Abente: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Silvia Crescioli: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Roman Laddach: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Pablo Romero-Clavijo: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Anthony Cheung: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Chara Stavraka: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Alicia M. Chenoweth: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Heng Sheng Sow: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Giulia Chiaruttini: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Amy E. Gilbert: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Tihomir Dodev: Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King’s College London
Alexander Koers: School of Biomedical Engineering and Imaging Sciences, King’s College London
Giulia Pellizzari: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Kristina M. Ilieva: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Francis Man: School of Biomedical Engineering and Imaging Sciences, King’s College London
Niwa Ali: Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London
Carl Hobbs: Wolfson Centre for Age-Related Diseases, King’s College London
Sara Lombardi: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Daniël A. Lionarons: Oncogene Biology Laboratory, The Francis Crick Institute
Hannah J. Gould: Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King’s College London
Andrew J. Beavil: Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King’s College London
Jenny L. C. Geh: Guy’s and St. Thomas’ NHS Foundation Trust
Alastair D. MacKenzie Ross: Guy’s and St. Thomas’ NHS Foundation Trust
Ciaran Healy: Guy’s and St. Thomas’ NHS Foundation Trust
Eduardo Calonje: St. John’s Institute of Dermatology, St. Thomas’ Hospital
Julian Downward: Oncogene Biology Laboratory, The Francis Crick Institute
Frank O. Nestle: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Sophia Tsoka: Faculty of Natural, Mathematical and Engineering Sciences, King’s College London, Bush House
Debra H. Josephs: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Philip J. Blower: School of Biomedical Engineering and Imaging Sciences, King’s College London
Panagiotis Karagiannis: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Katie E. Lacy: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
James Spicer: School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Hospital
Sophia N. Karagiannis: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London
Heather J. Bax: St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37811-3

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