| Literature DB >> 35301507 |
Iván Pérez-Núñez1, Catalina Rozalén1, José Ángel Palomeque1, Irene Sangrador1, Mariona Dalmau1, Laura Comerma2, Anna Hernández-Prat1, David Casadevall1, Silvia Menendez1, Daniel Dan Liu3,4, Minhong Shen3, Jordi Berenguer1, Irene Rius Ruiz5, Raul Peña1, José Carlos Montañés6, M Mar Albà6,7, Sarah Bonnin8, Julia Ponomarenko8,9, Roger R Gomis7,10,11, Juan Miguel Cejalvo11,12, Sonia Servitja11,13, Diego M Marzese14, Lluis Morey15,16, Leonie Voorwerk17, Joaquín Arribas1,5,7,11, Begoña Bermejo11,12, Marleen Kok17,18, Lajos Pusztai19, Yibin Kang3,20, Joan Albanell21,22,23,24, Toni Celià-Terrassa25,26.
Abstract
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.Entities:
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Year: 2022 PMID： 35301507 DOI： 10.1038/s43018-022-00339-4
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347