Nature cancer · 2022
LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Pérez-Núñez Iván, Rozalén Catalina, Palomeque José Ángel, Sangrador Irene, Dalmau Mariona, Comerma Laura, Hernández-Prat Anna, Casadevall David, Menendez Silvia, Liu Daniel Dan, Shen Minhong, Berenguer Jordi, Ruiz Irene Rius, Peña Raul, Montañés José Carlos, Albà M Mar, Bonnin Sarah, Ponomarenko Julia, Gomis Roger R, Cejalvo Juan Miguel, Servitja Sonia, Marzese Diego M, Morey Lluis, Voorwerk Leonie, Arribas Joaquín, Bermejo Begoña, Kok Marleen, Pusztai Lajos, Kang Yibin, Albanell Joan, Celià-Terrassa Toni
Аннотация
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.