دورية أكاديمية
Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state
| العنوان: | Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state |
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| المؤلفون: | Cerezo-Wallis, Daniela, Contreras-Alcalde, Marta, Troulé, Kevin, Catena, Xavier, Mucientes, Cynthia, Calvo, Tonantzin G., Cañón, Estela, Tejedo, Cristina, Pennacchi, Paula C., Hogan , Sabrina, Kölblinger, Peter, Tejero, Héctor, Chen, Andrew X., Ibarz, Nuria, Graña, Osvaldo, Martinez, Lola, Muñoz, Javier, Ortiz-Romero, Pablo, Rodríguez-Peralto, José L., Gómez-López, Gonzalo, Al-Shahrour, Fátima, Rabadán, Raúl, Levesque, Mitchell P., Olmeda, David, Soengas, María S. |
| المساهمون: | Ministerio de Economía y Competitividad (España), Melanoma Research Alliance (US), Worldwide Cancer Research, Fundación la Caixa, Asociación Española Contra el Cáncer, Ministerio de Sanidad (España), Fundación BBVA, Instituto de Salud Carlos III, Marie Curie Fellows Association, European Commission |
| بيانات النشر: | Springer Nature |
| سنة النشر: | 2020 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| مصطلحات موضوعية: | MIDKINE, Melanoma, Secretome, Immunotherapy, PDL1, PD1, Tumourassociated macrophages, Inflammation |
| الوصف: | An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/ anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas. ; M.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (SAF2017-89533-R), Team Science and Established Investigator awards by the Melanoma Research Alliance, and grants from Worldwide Cancer Research and Fundación ‘La Caixa’ Health Research 2019. M.S.S., P.O.-R. and J.L.R.-P. are funded by a collaborative grant from the Asociación Española Contra el Cáncer (AECC). D.O. is funded by grants from the Spanish Ministry of Health (AES-PIS PI18/1057) and ‘Fundación BBVA-Becas Leonardo a Investigadores y Creadores Culturales 2018’. D.C.-W. was a recipient of a predoctoral fellowship from Fundación ‘La Caixa’ and is currently funded by the AECC. The CNIO Proteomics Unit belongs to ProteoRed, PRB2-ISCIII, supported by grant PT13/0001. N.I. and J.M. are funded by SAF2013-45504-R (MINECO). J.M. is also supported by Ramón y Cajal Programme (MINECO) RYC-2012-10651. M.C.-A. and X.C. were funded by ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1078-8956 1546-170X |
| العلاقة: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-89533-R/ES/VISUALIZACION DE LAS METASTASIS DEL MELANOMA IN VIVO PARA LA IDENTIFICACION DE NUEVOS MARCADORES TUMORALES Y DIANAS TERAPEUTICAS/; info:eu-repo/grantAgreement/MINECO//RYC-2012-10651/ES/RYC-2012-10651/; info:eu-repo/grantAgreement/EC/H2020/641458; Postprint; https://doi.org/10.1038/s41591-020-1073-3Test; No; Nature Medicine 26: 1865–1877 (2020; http://hdl.handle.net/10261/344675Test; http://dx.doi.org/10.13039/501100003329Test; http://dx.doi.org/10.13039/100005190Test; http://dx.doi.org/10.13039/501100004587Test; http://dx.doi.org/10.13039/501100000780Test; http://dx.doi.org/10.13039/501100007287Test; http://dx.doi.org/10.13039/100007406Test |
| DOI: | 10.1038/s41591-020-1073-3 |
| DOI: | 10.13039/501100003329 |
| DOI: | 10.13039/100005190 |
| DOI: | 10.13039/501100004587 |
| DOI: | 10.13039/501100000780 |
| DOI: | 10.13039/501100007287 |
| DOI: | 10.13039/100007406 |
| الإتاحة: | https://doi.org/10.1038/s41591-020-1073-3Test https://doi.org/10.13039/501100003329Test https://doi.org/10.13039/100005190Test https://doi.org/10.13039/501100004587Test https://doi.org/10.13039/501100000780Test https://doi.org/10.13039/501100007287Test https://doi.org/10.13039/100007406Test http://hdl.handle.net/10261/344675Test |
| حقوق: | open |
| رقم الانضمام: | edsbas.14A8E11D |
| قاعدة البيانات: | BASE |
| تدمد: | 10788956 1546170X |
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| DOI: | 10.1038/s41591-020-1073-3 |