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

Fecha de publicación: 17/03/2022 Fecha Ahead of Print: 17/03/2022

Autores de INCLIVA

Juan Miguel Cejalvo Andujar

Autor
Begoña Bermejo De Las Heras

Autor

Participantes ajenos a INCLIVA

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
Servitja, Sonia
Marzese, Diego M
Morey, Lluis
Voorwerk, Leonie
Arribas, Joaquin
Kok, Marleen
Pusztai, Lajos
Kang, Yibin
Albanell, Joan
Celia-Terrassa, Toni

Grupos y Plataformas de I+D+i

Grupo de Investigación en Biología en Cáncer de mama

Leading Researcher

Pilar Eroles Asensio

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 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.