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

Iván Pérez-Núñez, Catalina Rozalén, José Ángel Palomeque, Irene Sangrador, Mariona Dalmau, Laura Comerma, Anna Hernández-Prat, David Casadevall, Silvia Menendez, Daniel Dan Liu, Minhong Shen, Jordi Berenguer, Irene Rius Ruiz, Raul Peña, José Carlos Montañés, M. Mar Albà, Sarah Bonnin, Julia Ponomarenko, Roger R. Gomis, Juan Miguel CejalvoSonia Servitja, Diego M. Marzese, Lluis Morey, Leonie Voorwerk, Joaquín Arribas, Begoña Bermejo, Marleen Kok, Lajos Pusztai, Yibin Kang, Joan Albanell, Toni Celià-Terrassa

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)355-370
Number of pages16
JournalNature Cancer
Volume3
Issue number3
DOIs
StatePublished - Mar 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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