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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, Daniel 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.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.issn 2662-1347
dc.identifier.uri http://hdl.handle.net/10230/55670
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.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Nat Cancer. 2022 Mar;3(3):355-70
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.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.identifier.doi http://dx.doi.org/10.1038/s43018-022-00339-4
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.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.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/acceptedVersion

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