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

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• dc.contributor.author Pérez-Núñez, Iván
• dc.contributor.author Rozalén, Catalina
• dc.contributor.author Palomeque, José Ángel
• dc.contributor.author Sangrador, Irene
• dc.contributor.author Dalmau, Mariona
• dc.contributor.author Comerma Blesa, Laura, 1983-
• dc.contributor.author Hernández Prat, Anna, 1984-
• dc.contributor.author Casadevall Aguilar, David
• dc.contributor.author Menendez Romero, Silvia
• dc.contributor.author Liu, Dan
• dc.contributor.author Berenguer De Felipe, Jordi
• dc.contributor.author Peña Arranz, Raúl, 1976-
• dc.contributor.author Montañés, José Carlos
• dc.contributor.author Albà Soler, Mar
• dc.contributor.author Bonnin, Sarah
• dc.contributor.author Ponomarenko, Julia
• dc.contributor.author Servitja Tormo, Sonia
• dc.contributor.author Arribas, Joaquín
• dc.contributor.author Albanell Mestres, Joan
• dc.contributor.author Celià-Terrassa, Toni
• dc.date.accessioned 2023-02-08T07:23:47Z
• dc.date.available 2023-02-08T07:23:47Z
• dc.date.issued 2022
• dc.description.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.
• dc.description.sponsorship This work was supported by the Instituto de Salud Carlos III-FSE (nos. MS17/00037 and PI18/00014) and the Cancer Research Institute, Clinic and Laboratory Integration Program (grant no. CRI2477 to T.C.-T). We also thank the AECC LAB (grant no. LABAE19007CELI) and the FERO foundation (to T.C.-T). This work was also supported by ISCIII (CIBERONC nos. CB16/12/00481, CB16/12/00241, PI18/00006 and PI21/00002), Generalitat de Catalunya (no. 2017 SGR 507) and the European Community through the Regional Development Funding Program to J. Albanell. Y.K. is supported by the Brewster Foundation, the Breast Cancer Research Foundation, the Susan G. Komen Foundation and the American Cancer Society. J. Arribas is funded by the Breast Cancer Research Foundation (no. BCRF-20-08), Instituto de Salud Carlos III (no. PI19/01181), Asociación Española Contra el Cáncer (no. GCAEC19017ARRI) and Fundación BBVA (no. CAIMI VHIO-FBBVA 2018-2021). M.M.A. is funded by MICINN and the Spanish Government (no. PGC2018-094091-B-I00). D.C. was funded by Instituto de Salud Carlos III (no. JR1800003). S.M. is funded by PERIS (no. SLT006/17/00040). The wotk of R.R.G. is funded by MICINN, the Spanish Government (no. PID2019-104948RB-I00) and the BBVA Foundation. S.B and J.P. acknowledge support from the Spanish Ministry of Science, the EMBL partnership and the CESO and CERCA Program.
• dc.format.mimetype application/pdf
• dc.identifier.citation Pérez-Núñez I, Rozalén C, Palomeque JÁ, Sangrador I, Dalmau M, Comerma L, et al. LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer. Nat Cancer. 2022 Mar;3(3):355-70. DOI: 10.1038/s43018-022-00339-4
• dc.identifier.doi http://dx.doi.org/10.1038/s43018-022-00339-4
• dc.identifier.issn 2662-1347
• dc.identifier.uri http://hdl.handle.net/10230/55670
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Cancer. 2022 Mar;3(3):355-70
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-094091-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104948RB-I00
• dc.rights © Springer Nature Publishing AG [Pérez-Núñez I, Rozalén C, Palomeque JÁ, Sangrador I, Dalmau M, Comerma L, et al. LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer. Nat Cancer. 2022 Mar;3(3):355-70. DOI: 10.1038/s43018-022-00339-4] [http://dx.doi.org/10.1038/s43018-022-00339-4]
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Breast cancer
• dc.subject.keyword Cancer
• dc.subject.keyword Cancer immunotherapy
• dc.subject.keyword Cancer stem cells
• dc.subject.keyword Immunoediting
• dc.title LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion