Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response

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dc.authorid0000-0002-7412-5610
dc.contributor.authorWofford, Wyatt
dc.contributor.authorKim, Jisun
dc.contributor.authorKim, Dosung
dc.contributor.authorJanneh, Alhaji H.
dc.contributor.authorLee, Han Gyul
dc.contributor.authorAtılgan, Cansu
dc.contributor.authorOleinik, Natalia
dc.contributor.authorKassir, Mohamed Faisal
dc.contributor.authorSaatçi, Özge
dc.contributor.authorChakraborty, Paramita
dc.contributor.authorTokat, Ünal Metin
dc.contributor.authorGencer, Salih
dc.contributor.authorHowley, Breege
dc.contributor.authorHowe, Philip
dc.contributor.authorMehrotra, Shikhar
dc.contributor.authorŞahin, Özgür
dc.contributor.authorÖğretmen, Besim
dc.date.accessioned2024-08-08T07:48:29Z
dc.date.available2024-08-08T07:48:29Z
dc.date.issued2024
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı
dc.description.abstractProgrammed 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 ? 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 ?-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.
dc.identifier.citationWofford, 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
dc.identifier.doi10.1016/j.celrep.2024.114532
dc.identifier.issn2211-1247
dc.identifier.issue8
dc.identifier.pmid39046874
dc.identifier.scopus2-s2.0-85199255949
dc.identifier.scopusqualityQ1
dc.identifier.urihttp://dx.doi.org/10.1016/j.celrep.2024.114532
dc.identifier.urihttps://hdl.handle.net/20.500.12511/12769
dc.identifier.volume43
dc.identifier.wos001284589700001en_US
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorGencer, Salih
dc.language.isoen
dc.relation.ispartofCell Reportsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectCeramide
dc.subjectCers4
dc.subjectCP: Cancer
dc.subjectCP: Metabolism
dc.subjectImmunotherapy
dc.subjectMetastasis
dc.subjectPD-L1
dc.subjectSonic Hedgehog
dc.subjectSphingolipid
dc.titleAlterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response
dc.typeArticle

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