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 language | English (US) |
|---|---|
| Pages (from-to) | 355-370 |
| Number of pages | 16 |
| Journal | Nature Cancer |
| Volume | 3 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2022 |
All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
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In: Nature Cancer, Vol. 3, No. 3, 03.2022, p. 355-370.
Research output: Contribution to journal › Article › peer-review
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 - Funding Information: 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. The TONIC study was funded by BMS and the Dutch Cancer Society, to M.K. L.P. is funded by the Breast Cancer Research Foundation. We thank the Michelangelo Foundation and L. Gianni who authorized the use of NeoTRIP samples. We thank T. Morell, Cafè Plaça and Sa Pobla participants for donations. We thank A. Bigas and L. Espinosa for scientific discussions and critical advice. We thank A. Ribas for facilitating clinical datasets. We thank F. Olivares from the Hospital del Mar Pathology unit. We thank CRG/UPF for flow cytometry assistance, especially O. Fornas, E. Julià, A. Bote and E. Ramírez; and the CRG genomics and bioinformatics units for assistance. We thank J. Swoger and G. Shah from the EMBL-Barcelona Mesoscopic Imaging Facility for imaging assistance. The animal cartoons in Figs. and and Extended Data Fig. were created with BioRender ( https://biorender.com/ ). We thank L. M. Wakefield for sharing reagents for the SORE6-GFP reporter; and F. Pajonk for the pQCXIN/ZsGreen reporter. Funding Information: 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), Asociacio?n Espan?ola Contra el Ca?ncer (no. GCAEC19017ARRI) and Fundaci?n 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. The TONIC study was funded by BMS and the Dutch Cancer Society, to M.K. L.P. is funded by the Breast Cancer Research Foundation. We thank the Michelangelo Foundation and L. Gianni who authorized the use of NeoTRIP samples. We thank T. Morell, Caf? Pla?a and Sa Pobla participants for donations. We thank A. Bigas and L. Espinosa for scientific discussions and critical advice. We thank A. Ribas for facilitating clinical datasets. We thank F. Olivares from the Hospital del Mar Pathology unit. We thank CRG/UPF for flow cytometry assistance, especially O. Fornas, E. Juli?, A. Bote and E. Ram?rez; and the CRG genomics and bioinformatics units for assistance. We thank J. Swoger and G. Shah from the EMBL-Barcelona Mesoscopic Imaging Facility for imaging assistance. The animal cartoons in Figs. 6d and 7d and Extended Data Fig. 6k were created with BioRender (https://biorender.com/). We thank L. M. Wakefield for sharing reagents for the SORE6-GFP reporter; and F. Pajonk for the pQCXIN/ZsGreen reporter. Funding Information: IMIM has filed a patent on the findings based on this study, with T.C.-T., J. Albanell, I.P.-N. and C.R. are named as coinventors. J. Albanell has received consulting fees and honoraria from Seagen, Pfizer, AstraZeneca, Lilly, Merck, Roche, Gilead, Novartis and Daiichi-Sankyo, receives royalties from a licensed patent to Biocartis and holds stock options from Inbiomotion. J. Arribas reports grants from Roche, Synthon/Biondys and Molecular Partners; and grants and personal fees from Menarini and Mnemo during the conduct of the study. J. Arribas has a patent for EP 0930183.5 issued, licensed and with royalties paid, a patent for P200801652 issued, licensed and with royalties paid, and a patent for EP20382457.8 pending, licensed and with royalties paid. L.C. reports being an advisory board member and receiving honoraria as speaker’s bureau from Roche. L.P. has received consulting fees and honoraria from Seagen, Pfizer, Astra Zeneca, Merck, Novartis, Bristol Myers Squibb, Genentech, Eisai, Pieris, Immunomedics, Clovis, Syndax, H3Bio, Radius Health, Personalis, Natera and Daiichi; and institutional research funding from Seagen, AstraZeneca, Merck, Pfizer and Bristol Myers Squibb. The remaining authors declare no competing interest. 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.
UR - http://www.scopus.com/inward/record.url?scp=85126449954&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85126449954&partnerID=8YFLogxK
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 -