NF-κB and TET2 promote macrophage reprogramming in hypoxia that overrides the immunosuppressive effects of the tumor microenvironment
de la Calle-Fabregat, Carlos (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Calafell-Segura, Josep (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Gardet, M. (INSERM UMR1015. Gustave Roussy Cancer Campus)
Dunsmore, G. (INSERM UMR1015. Gustave Roussy Cancer Campus)
Mulder, K. (INSERM UMR1015. Gustave Roussy Cancer Campus)
Ciudad, Laura (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Silvin, A. (INSERM UMR1015. Gustave Roussy Cancer Campus)
Moreno-Càceres, Joaquim (Hospital Universitari de Bellvitge)
Corbí, Á.L. (Centro de Investigaciones Biológicas (CSIC))
Muñoz-Pinedo, Cristina (Hospital Universitari de Bellvitge)
Michels, J. (Gustave Roussy)
Gouy, S. (Gustave Roussy)
Dutertre, C.A. (INSERM UMR1015. Gustave Roussy Cancer Campus)
Rodríguez-Ubreva, Javier (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ginhoux, F. (INSERM UMR1015. Gustave Roussy Cancer Campus)
Ballestar, Esteban (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Universitat Autònoma de Barcelona

Date:	2024
Abstract:	Macrophages orchestrate tissue homeostasis and immunity. In the tumor microenvironment (TME), macrophage presence is largely associated with poor prognosis because of their reprogramming into immunosuppressive cells. We investigated the effects of hypoxia, a TME-associated feature, on the functional, epigenetic, and transcriptional reprogramming of macrophages and found that hypoxia boosts their immunogenicity. Hypoxic inflammatory macrophages are characterized by a cluster of proinflammatory genes undergoing ten-eleven translocation-mediated DNA demethylation and overexpression. These genes are regulated by NF-κB, while HIF1α dominates the transcriptional reprogramming, demonstrated through ChIP-seq and pharmacological inhibition. In bladder and ovarian carcinomas, hypoxic inflammatory macrophages are enriched in immune-infiltrated tumors, correlating with better patient prognoses. Coculture assays and cell-cell communication analyses support that hypoxic-activated macrophages enhance T cell-mediated responses. The NF-κB-associated hypomethylation signature is displayed by a subset of hypoxic inflammatory macrophages, isolated from ovarian tumors. Our results challenge paradigms regarding the effects of hypoxia on macrophages and highlight actionable target cells to modulate anticancer immune responses.
Grants:	Agencia Estatal de Investigación PID2020-117212RB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01213
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Associated feature ; DNA demethylation ; Epigenetics ; Functionals ; Homoeostasis ; Immunogenicity ; Immunosuppressive effects ; Overexpressions ; Proinflammatory ; Tumor microenvironments ; Animals ; Cell Hypoxia ; Cell Line, Tumor ; Cellular Reprogramming ; Dioxygenases ; DNA Methylation ; DNA-Binding Proteins ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; Macrophages ; Mice ; NF-kappa B ; Ovarian Neoplasms ; Proto-Oncogene Proteins ; Tumor Microenvironment ; Urinary Bladder Neoplasms
Published in:	Science advances, Vol. 10 Núm. 38 (20 2024) , p. eadq5226, ISSN 2375-2548

DOI: 10.1126/sciadv.adq5226
PMID: 39292770

16 p, 5.1 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
Articles > Research articles
Articles > Published articles