dc.contributor.author | Wofford, Wyatt | |
dc.contributor.author | Kim, Jisun | |
dc.contributor.author | Kim, Dosung | |
dc.contributor.author | Janneh, Alhaji H. | |
dc.contributor.author | Lee, Han Gyul | |
dc.contributor.author | Atılgan, Cansu | |
dc.contributor.author | Oleinik, Natalia | |
dc.contributor.author | Kassir, Mohamed Faisal | |
dc.contributor.author | Saatçi, Özge | |
dc.contributor.author | Chakraborty, Paramita | |
dc.contributor.author | Tokat, Ünal Metin | |
dc.contributor.author | Gencer, Salih | |
dc.contributor.author | Howley, Breege | |
dc.contributor.author | Howe, Philip | |
dc.contributor.author | Mehrotra, Shikhar | |
dc.contributor.author | Şahin, Özgür | |
dc.contributor.author | Öğretmen, Besim | |
dc.date.accessioned | 2024-08-08T07:48:29Z | |
dc.date.available | 2024-08-08T07:48:29Z | |
dc.date.issued | 2024 | en_US |
dc.identifier.citation | Wofford, W., Kim, J., Kim, D., Janneh, A. H., Lee, H. G., Atılgan, C. ... Öğretmen, B. (2024). Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response. Cell Reports, 43(8). http://dx.doi.org/10.1016/j.celrep.2024.114532 | en_US |
dc.identifier.issn | 2211-1247 | |
dc.identifier.uri | http://dx.doi.org/10.1016/j.celrep.2024.114532 | |
dc.identifier.uri | https://hdl.handle.net/20.500.12511/12769 | |
dc.description.abstract | Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ regulatory T cells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4−/− were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs. | en_US |
dc.language.iso | eng | en_US |
dc.rights | info:eu-repo/semantics/openAccess | en_US |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | * |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Ceramide | en_US |
dc.subject | Cers4 | en_US |
dc.subject | CP: Cancer | en_US |
dc.subject | CP: Metabolism | en_US |
dc.subject | Immunotherapy | en_US |
dc.subject | Metastasis | en_US |
dc.subject | PD-L1 | en_US |
dc.subject | Sonic Hedgehog | en_US |
dc.subject | Sphingolipid | en_US |
dc.title | Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response | en_US |
dc.type | article | en_US |
dc.relation.ispartof | Cell Reports | en_US |
dc.department | İstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü | en_US |
dc.department | İstanbul Medipol Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı | en_US |
dc.authorid | 0000-0002-7412-5610 | en_US |
dc.identifier.volume | 43 | en_US |
dc.identifier.issue | 8 | en_US |
dc.relation.publicationcategory | Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı | en_US |
dc.identifier.doi | 10.1016/j.celrep.2024.114532 | en_US |
dc.institutionauthor | Gencer, Salih | |
dc.identifier.scopus | 2-s2.0-85199255949 | en_US |
dc.identifier.pmid | 39046874 | en_US |
dc.identifier.scopusquality | Q1 | en_US |