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

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 - Palhares, Lais C G F

AU - Mele, Silvia

AU - Nakamura, Mano

AU - López-Abente, Jacobo

AU - Crescioli, Silvia

AU - Laddach, Roman

AU - Romero-Clavijo, Pablo

AU - Cheung, Anthony

AU - Stavraka, Chara

AU - Chenoweth, Alicia M

AU - Sow, Heng Sheng

AU - Chiaruttini, Giulia

AU - Gilbert, Amy E

AU - Dodev, Tihomir

AU - Koers, Alexander

AU - Pellizzari, Giulia

AU - Ilieva, Kristina M

AU - Man, Francis

AU - Ali, Niwa

AU - Hobbs, Carl

AU - Lombardi, Sara

AU - Lionarons, Daniël A

AU - Gould, Hannah J

AU - Beavil, Andrew J

AU - Geh, Jenny L C

AU - MacKenzie Ross, Alastair D

AU - Healy, Ciaran

AU - Calonje, Eduardo

AU - Downward, Julian

AU - Nestle, Frank O

AU - Tsoka, Sophia

AU - Josephs, Debra H

AU - Blower, Philip J

AU - Karagiannis, Panagiotis

AU - Lacy, Katie E

AU - Spicer, James

AU - Karagiannis, Sophia N

AU - Bax, Heather J

N1 - © 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.

U2 - 10.1038/s41467-023-37811-3

DO - 10.1038/s41467-023-37811-3

M3 - SCORING: Journal article

C2 - 37185332

VL - 14

SP - 2192

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -