TY - JOUR
T1 - Anti-cancer Pro-inflammatory Effects of an IgE Antibody Targeting the Melanoma-associated Antigen Chondroitin Sulfate Proteoglycan 4
AU - Chauhan, Jitesh
AU - Grandits, Melanie
AU - Gusmao Ferreira, Lais Cristina
AU - Mele, Silvia
AU - Nakamura, Mano
AU - Lopez-Abente Muroz, Jacobo
AU - Crescioli, Silvia
AU - Laddach, Roman
AU - Romero Clavijo, Pablo
AU - Cheung, Anthony
AU - Stavraka, Chara
AU - Chenoweth, Alicia
AU - Sow, Heng Sheng
AU - Chiaruttini, Giulia
AU - Gilbert, Amy
AU - Dodev, Tihomir
AU - Koers, Alex
AU - Pellizzari, Giulia
AU - Ilieva, Kristina
AU - Man, Francis
AU - Ali, Niwa
AU - Hobbs, Carl
AU - Lombardi, Sara
AU - Lionarons, Daniël A.
AU - Gould, Hannah J.
AU - Beavil, Andrew
AU - Geh, Jenny L. C.
AU - MacKenzie Ross, Alastair D
AU - Healy, Ciaran
AU - Calonje, Eduardo
AU - Downward, Julian
AU - Nestle, Frank
AU - Tsoka, Sophia
AU - Josephs, Debra
AU - Blower, Philip
AU - Karagiannis, Panagiotis
AU - Lacy, Katie E.
AU - Spicer, James
AU - Karagiannis, Sophia N
AU - Bax, Heather
N1 - Funding Information:
The authors acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility team at Guy’s and St Thomas’ NHS Foundation Trust for flow cytometry facilities and assistance and Ms. Debbie Finch at the Cancer Research UK King’s Health Partners Centre at King’s College London for immunohistochemistry support. We thank all healthy volunteers and patients who participated in this study, as well as and colleagues from Guy’s and St Thomas’ Oncology & Haematology Clinical Trials (OHCT), especially Agnieszka Zielonka, Harriet Gilbert-Jones, Malahat Khaula, and Anna Black for their assistance. The authors are solely responsible for the decision to publish, and the preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006; S.N.K.). The authors acknowledge support from Cancer Research UK (C30122/A11527; C30122/A15774; J.S., S.N.K., H.J.B., P.J.B., and H.J.G.); the Medical Research Council (MR/L023091/1; S.N.K., F.O.N., and J.S.); Innovate UK (51746; S.N.K.); the Guy’s and St Thomas’s Foundation Trust Charity Melanoma Special Fund (573; S.N.K. and K.E.L.); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587; J.S.); The Rotary Foundation of Rotary International (M.N.); the Inman Charity (S.N.K. and G.P.); Breast Cancer Now (147; KCL-BCN-Q3; S.N.K.); the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135; J.S.); Cancer Research UK City of London Centre—Studentships award (C7893/A31530; J.D., S.N.K., J.S., and P.R.-C.).
Funding Information:
The authors acknowledge the Biomedical Research Centre (BRC) Immune Monitoring Core Facility team at Guy’s and St Thomas’ NHS Foundation Trust for flow cytometry facilities and assistance and Ms. Debbie Finch at the Cancer Research UK King’s Health Partners Centre at King’s College London for immunohistochemistry support. We thank all healthy volunteers and patients who participated in this study, as well as and colleagues from Guy’s and St Thomas’ Oncology & Haematology Clinical Trials (OHCT), especially Agnieszka Zielonka, Harriet Gilbert-Jones, Malahat Khaula, and Anna Black for their assistance. The authors are solely responsible for the decision to publish, and the preparation of the manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006; S.N.K.). The authors acknowledge support from Cancer Research UK (C30122/A11527; C30122/A15774; J.S., S.N.K., H.J.B., P.J.B., and H.J.G.); the Medical Research Council (MR/L023091/1; S.N.K., F.O.N., and J.S.); Innovate UK (51746; S.N.K.); the Guy’s and St Thomas’s Foundation Trust Charity Melanoma Special Fund (573; S.N.K. and K.E.L.); CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre (C10355/A15587; J.S.); The Rotary Foundation of Rotary International (M.N.); the Inman Charity (S.N.K. and G.P.); Breast Cancer Now (147; KCL-BCN-Q3; S.N.K.); the Cancer Research UK King’s Health Partners Centre at King’s College London (C604/A25135; J.S.); Cancer Research UK City of London Centre—Studentships award (C7893/A31530; J.D., S.N.K., J.S., and P.R.-C.).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4/25
Y1 - 2023/4/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85154551617&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-37811-3
DO - https://doi.org/10.1038/s41467-023-37811-3
M3 - Article
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2192
ER -