دورية أكاديمية
Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.
| العنوان: | Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells. |
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| المؤلفون: | Gómez-Aleza, Clara, Nguyen, Bastien, Yoldi, Guillermo, Ciscar, Marina, Barranco, Alexandra, Hernández-Jiménez, Enrique, Maetens, Marion, Salgado, Roberto, Zafeiroglou, Maria, Pellegrini, Pasquale, Venet, David, Garaud, Soizic, Trinidad, Eva M, Benítez, Sandra, Vuylsteke, Peter, Polastro, Laura, Wildiers, Hans, Simon, Philippe, Lindeman, Geoffrey, Larsimont, Denis, Van den Eynden, Gert, Velghe, Chloé, Rothé, Françoise, Willard-Gallo, Karen, Michiels, Stefan, Muñoz, Purificación, Walzer, Thierry, Planelles, Lourdes, Penninger, Josef, Azim, Hatem A, Loi, Sherene, Piccart, Martine, Sotiriou, Christos, González-Suárez, Eva |
| المساهمون: | Institut Jules Bordet, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Unión Europea. Comisión Europea. European Research Council (ERC), Fundación La Marató TV3, National Fund for Research (Francia), Breast Cancer Research Foundation |
| بيانات النشر: | Nature Publishing Group |
| سنة النشر: | 2020 |
| المجموعة: | REPISALUD (REPositorio Institucional en SALUD del Instituto de Salud Carlos III - ISCIII) |
| مصطلحات موضوعية: | Immunity, Signal Transduction, Adult, Animals, Breast Neoplasms, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Chemokines, Denosumab, Female, Humans, Immunosuppression, Immunotherapy, Inflammation Mediators, Lymphocytes, Tumor-Infiltrating, Mice, Inbred C57BL, Middle Aged, Models, Biological, Myeloid Cells, Neoplasm Staging, Neutrophils, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B |
| الوصف: | Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8+ T cells, and reduces macrophage and neutrophil infiltration. CD8+ T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8+ T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy. ; We thank the patients who contributed to this study and acknowledge the clinical staff for their dedication. The D-BEYOND clinical trial was sponsored by Jules Bordet Institute, which was responsible for the management of the study. This work was supported by grants to E. Gonzalez-Suarez by MICINN (SAF2014-55997-R, SAF201786117-R) co-funded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 682935), and Fundacio La Marato de TV3. We thank CERCA Programme/Generalitat de Catalunya for ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2041-1723 |
| العلاقة: | https://doi.org/10.1038/s41467-020-20138-8Test.; info:eu-repo/grantAgreement/ES/SAF2014-55997-R; info:eu-repo/grantAgreement/ES/SAF201786117-R; info:eu-repo/grantAgreement/EC/H2020/682935; Nat Commun. 2020;11(1):6335.; http://hdl.handle.net/20.500.12105/12178Test; Nature communications |
| DOI: | 10.1038/s41467-020-20138-8 |
| الإتاحة: | https://doi.org/20.500.12105/12178Test https://doi.org/10.1038/s41467-020-20138-8Test https://hdl.handle.net/20.500.12105/12178Test |
| حقوق: | http://creativecommons.org/licenses/by-nc-sa/4.0Test/ ; Atribución-NoComercial-CompartirIgual 4.0 Internacional ; open access |
| رقم الانضمام: | edsbas.EF7673A0 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 20411723 |
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| DOI: | 10.1038/s41467-020-20138-8 |