TY - JOUR
T1 - LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer
AU - Pérez-Núñez, Iván
AU - Rozalén, Catalina
AU - Palomeque, José Ángel
AU - Sangrador, Irene
AU - Dalmau, Mariona
AU - Comerma, Laura
AU - Hernández-Prat, Anna
AU - Casadevall, David
AU - Menendez, Silvia
AU - Liu, Daniel Dan
AU - Shen, Minhong
AU - Berenguer, Jordi
AU - Ruiz, Irene Rius
AU - Peña, Raul
AU - Montañés, José Carlos
AU - Albà, M. Mar
AU - Bonnin, Sarah
AU - Ponomarenko, Julia
AU - Gomis, Roger R.
AU - Cejalvo, Juan Miguel
AU - Servitja, Sonia
AU - Marzese, Diego M.
AU - Morey, Lluis
AU - Voorwerk, Leonie
AU - Arribas, Joaquín
AU - Bermejo, Begoña
AU - Kok, Marleen
AU - Pusztai, Lajos
AU - Kang, Yibin
AU - Albanell, Joan
AU - Celià-Terrassa, Toni
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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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U2 - 10.1038/s43018-022-00339-4
DO - 10.1038/s43018-022-00339-4
M3 - Article
C2 - 35301507
AN - SCOPUS:85126449954
SN - 2662-1347
VL - 3
SP - 355
EP - 370
JO - Nature Cancer
JF - Nature Cancer
IS - 3
ER -