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

TitleLCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer.
Publication TypeJournal Article
Year of Publication2022
AuthorsPérez-Núñez, I, Rozalén, C, Palomeque, JÁngel, Sangrador, I, Dalmau, M, Comerma, L, Hernández-Prat, A, Casadevall, D, Menendez, S, Liu, DDan, Shen, M, Berenguer, J, Ruiz, IRius, Peña, R, Montañés, JCarlos, M Albà, M, Bonnin, S, Ponomarenko, J, Gomis, RR, Cejalvo, JMiguel, Servitja, S, Marzese, DM, Morey, L, Voorwerk, L, Arribas, J, Bermejo, B, Kok, M, Pusztai, L, Kang, Y, Albanell, J, Celià-Terrassa, T
JournalNat Cancer
Volume3
Issue3
Pagination355-370
Date Published2022 03
ISSN2662-1347
KeywordsHumans, Immune Checkpoint Inhibitors, Immunotherapy, Interferons, Melanoma, Repressor Proteins, Skin Neoplasms, Triple Negative Breast Neoplasms
Abstract

<p>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 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.</p>

DOI10.1038/s43018-022-00339-4
Alternate JournalNat Cancer
PubMed ID35301507