Inhibition of furin in CAR macrophages directs them toward a proinflammatory phenotype and enhances their antitumor activities

Autor: Lydia Ziane-Chaouche, Antonella Raffo-Romero, Nawale Hajjaji, Firas Kobeissy, Donna Pinheiro, Soulaimane Aboulouard, Adeline Cozzani, Suman Mitra, Isabelle Fournier, Dasa Cizkova, Michel Salzet, Marie Duhamel
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Cell Death and Disease, Vol 15, Iss 12, Pp 1-16 (2024)
Druh dokumentu: article
ISSN: 2041-4889
DOI: 10.1038/s41419-024-07267-4
Popis: Abstract Chimeric antigen receptor (CAR)-T-cell therapy has revolutionized cellular immunotherapy, demonstrating remarkable efficacy in hematological cancers. However, its application in solid tumors faces significant challenges, including limited T-cell infiltration and tumor-induced immunosuppression. Given the prominent role of macrophages in the tumor microenvironment, their phenotypic plasticity and inherent antitumor properties, such as phagocytosis, offer a promising avenue for therapeutic intervention. This study focuses on the development of a second generation of CAR macrophages (CAR-Ms). We elucidated the role of the proprotein convertase furin in macrophages, demonstrating its overexpression in the presence of tumor cells. Importantly, furin inhibition maintains a proinflammatory macrophage phenotype, potentially redirecting them towards an antitumor state. Compared to furin-expressing counterparts, furin-inhibited CAR-Ms exhibited heightened antitumor phagocytic activity against breast cancer cells and ex vivo patient-derived tumoroids. Notably, they sustained a persistent proinflammatory profile, indicative of enhanced tumoricidal potential. Additionally, furin-inhibited CAR-Ms secreted factors that promote T-cell activation, offering a means to modulate the tumor microenvironment. In summary, our work highlights the translational potential of furin-inhibited CAR-Ms as a potent cellular therapy to mitigate macrophage exhaustion within the tumor environment. By capitalizing on macrophage-mediated antitumor responses, these findings pave the way for the development of second-generation CAR-M therapeutic strategies tailored for solid tumors.
Databáze: Directory of Open Access Journals
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