LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therap...

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Detalhes bibliográficos
Autores: Pérez-Núñez, Iván, Rozalén, Catalina, Palomeque, José Ángel, Sangrador, Irene, Dalmau, Mariona, Comerma Blesa, Laura, 1983-, Hernández Prat, Anna, 1984-, Casadevall Aguilar, David, Menendez Romero, Silvia, Liu, Dan, Berenguer De Felipe, Jordi, Peña Arranz, Raúl, 1976-, Montañés, José Carlos, Albà Soler, Mar, Bonnin, Sarah, Ponomarenko, Julia, Servitja Tormo, Sonia, Arribas, Joaquín, Albanell Mestres, Joan, Celià-Terrassa, Toni
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2022
País:España
Recursos:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/55670
Acesso em linha:http://hdl.handle.net/10230/55670
http://dx.doi.org/10.1038/s43018-022-00339-4
Access Level:acceso abierto
Palavra-chave:Breast cancer
Cancer
Cancer immunotherapy
Cancer stem cells
Immunoediting
Descrição
Resumo:Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.

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