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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Bibliographic Details
Authors: Perez-Nunez, Ivan, Rozalen, Catalina, Palomeque, Jose Angel, Sangrador, Irene, Dalmau, Mariona, Comerma, Laura, Hernandez-Prat, Anna, Casadevall, David, Menendez, Silvia, Liu, Daniel Dan, Shen, Minhong, Berenguer, Jordi, Ruiz, Irene Rius, Pena, Raul, Montanes, Jose Carlos, Alba, M Mar, Bonnin, Sarah, Ponomarenko, Julia, Gomis, Roger R, Cejalvo, Juan Miguel, Servitja, Sonia, Marzese, Diego M, Morey, Lluis, Voorwerk, Leonie, Arribas, Joaquin, Bermejo, Begona, Kok, Marleen, Pusztai, Lajos, Kang, Yibin, Albanell, Joan, Celia-Terrassa, Toni
Format: article
Status:Published version
Publication Date:2022
Country:España
Institution:INCLIVA
Repository:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p16471
Online Access:https://incliva.portalinvestigacion.com/publicaciones/16471
Access Level:Open access
Description
Summary: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 LCOR(low) 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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