Macrophage CD5L is a target for cancer immunotherapy
Sanchez-Moral, Lidia (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Paul, Tony (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Martori Muntsant, Clara (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Font-Díaz, Joan (Universitat de Barcelona)
Sanjurjo, Lucía (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Aran, Gemma (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Téllez, Érica (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Blanco, Julià (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Carrillo, Jorge (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Ito, Masaoki (Hiroshima University)
Tuttolomondo, Martina (University of Southern Denmark)
Ditzel, Henrik J. (Odense University Hospital (Dinamarca))
Fumagalli, Caterina (Institut d'Investigació Biomèdica Sant Pau)
Tapia, Gustavo (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Sidorova, Julia (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Masnou, Helena (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Fernández-Sanmartín, Marco-Antonio (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Lozano, Juan-José (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Vilaplana, Cristina (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Rodriguez-Cortes, Alheli (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Armengol, Carolina (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Valledor, Annabel F. (Universitat de Barcelona)
Kremer, Leonor (Centro Nacional de Biotecnología (Espanya))
Sarrias, Maria-Rosa (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)

Data:	2023
Resum:	Reprogramming of immunosuppressive tumor-associated macrophages (TAMs) presents an attractive therapeutic strategy in cancer. The aim of this study was to explore the role of macrophage CD5L protein in TAM activity and assess its potential as a therapeutic target. Monoclonal antibodies (mAbs) against recombinant CD5L were raised by subcutaneous immunization of BALB/c mice. Peripheral blood monocytes were isolated from healthy donors and stimulated with IFN/LPS, IL4, IL10, and conditioned medium (CM) from different cancer cell lines in the presence of anti-CD5L mAb or controls. Subsequently, phenotypic markers, including CD5L, were quantified by flow cytometry, IF and RT-qPCR. Macrophage CD5L protein expression was studied in 55 human papillary lung adenocarcinoma (PAC) samples by IHC and IF. Anti-CD5L mAb and isotype control were administered intraperitoneally into a syngeneic Lewis Lung Carcinoma mouse model and tumor growth was measured. Tumor microenvironment (TME) changes were determined by flow cytometry, IHC, IF, Luminex, RNAseq and RT-qPCR. Cancer cell lines CM induced an immunosuppressive phenotype (increase in CD163, CD206, MERTK, VEGF and CD5L) in cultured macrophages. Accordingly, high TAM expression of CD5L in PAC was associated with poor patient outcome (Log-rank (Mantel-Cox) test p = 0. 02). We raised a new anti-CD5L mAb that blocked the immunosuppressive phenotype of macrophages in vitro. Its administration in vivo inhibited tumor progression of lung cancer by altering the intratumoral myeloid cell population profile and CD4 + T-cell exhaustion phenotype, thereby significantly modifying the TME and increasing the inflammatory milieu. CD5L protein plays a key function in modulating the activity of macrophages and their interactions within the TME, which supports its role as a therapeutic target in cancer immunotherapy. For a full list of funding bodies, please see the Acknowledgements.
Ajuts:	Instituto de Salud Carlos III PI19/00523 Agencia Estatal de Investigación PID2020-119875RB-I00
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	CD5L ; Immunotherapy ; Lung adenocarcinoma ; Macrophage ; Monoclonal antibody ; Scavenger receptor cysteine rich
Publicat a:	EBioMedicine, Vol. 91 (april 2023) , ISSN 2352-3964

DOI: 10.1016/j.ebiom.2023.104555
PMID: 37054630

22 p, 4.7 MB

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