FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4200015656> ?p ?o ?g. }

• W4200015656 abstract "BRD4 is a member of the family of BET proteins that act as epigenetic readers and regulators of gene transcription. BRD4 is a known driver of tumor growth via enhancement of transcription of oncogenes such as Myc. More recent evidence also suggests a role of BRD4 in T cells. T cell differentiation and T cell exhaustion is epigenetically regulated and BRD4 has been associated with T cell differentiation. Available small molecule inhibitors of BET proteins do not target BRD4 specifically, but also inhibit other members of the BET protein family. We therefore investigated the effects of BRD4 silencing on T cells with the INTASYL™ compound PH-894, a self-delivering RNAi specifically targeting BRD4. INTASYL self-delivering RNAi molecules consist of an asymmetric duplex structure, a small duplex region (≤ 15 base pairs), a single-stranded phosphorothioate tail, and chemical modifications to confer stability, hydrophobicity, and efficient cellular uptake. Primary human T cells from healthy donors, either unstimulated or activated by OKT3 or anti-CD3/CD28 beads, were treated with PH-894. Additional studies were performed with CD8⁺ T cells magnetically sorted from primary human T cells. Silencing of BRD4 mRNA was assessed by RT-qPCR, and protein by flow cytometry. Phenotypic markers of T cell activation, differentiation and function were assessed by flow cytometry and cytokine secretion by cytometric bead array. Expanded and PH-894-treated CD8⁺ T cells were studied for IFNγ production upon coculture with allogeneic melanoma cell lines. Silencing of BRD4 mRNA and protein by PH-894 was concentration dependent and durable for up to 10 days in activated and naïve T cells. Silencing was specific for BRD4 with no effect on BRD2 or BRD3 expression. In activated T cells there was a suppression of IL-10 secretion and no effect on inflammatory cytokine levels. Markers of T cell activation were elevated on naïve PH-894-treated T cells with a shift to an increased CD8⁺/CD4⁺ ratio. In addition, BRD4 silencing in activated CD8⁺ T cells coincided with a decreased expression of transcription factors typically induced immediately upon TCR activation and are known drivers of T cell differentiation towards an effector phenotype. Moreover, CD8⁺ T cells expanded in the presence of PH-894 produced increased levels of IFNγ when cocultured with two allogeneic melanoma cell lines. These data translated <i>in vivo</i> with PH-894 treatment eliciting a dose associated inhibition of tumor growth in a CT26 murine colon carcinoma model. <i>Ex vivo</i> analysis of tumors found PH-894 efficacy was associated with decreased expression of BRD4 in tumor infiltrating CD3 T cells, and a reduction of Foxp3^hi CD25^hi CD4⁺ CD3⁺ Tregs, compared with control tumors. Specific silencing of BRD4 with PH-894 resulted in phenotypic changes on T cells associated with T cell activation and reduced immunosuppression. These data suggest that BRD4 not only plays a role on tumor cells but can also regulate T cell function and that PH-894 can reprogram T cells to provide enhanced immunotherapeutic activity. <b>Citation Format:</b> Melissa Maxwell, Daisuke Ujiie, Benjamin Cuiffo, Brianna Rivest, Dingxue Yan, James Cardia, Jeroen Melief, Rolf Kiessling, Simon P. Fricker. Targeting BRD4 in T cells with self-delivering RNAi PH-894 for immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P109." @default.
• W4200015656 created "2021-12-31" @default.
• W4200015656 creator A5012932735 @default.
• W4200015656 creator A5024915505 @default.
• W4200015656 creator A5028287372 @default.
• W4200015656 creator A5030738623 @default.
• W4200015656 creator A5032271120 @default.
• W4200015656 creator A5057916077 @default.
• W4200015656 creator A5081951424 @default.
• W4200015656 creator A5083071027 @default.
• W4200015656 creator A5088833390 @default.
• W4200015656 date "2021-12-01" @default.
• W4200015656 modified "2023-10-18" @default.
• W4200015656 title "Abstract P109: Targeting BRD4 in T cells with self-delivering RNAi PH-894 for immunotherapy" @default.
• W4200015656 doi "https://doi.org/10.1158/1535-7163.targ-21-p109" @default.
• W4200015656 hasPublicationYear "2021" @default.
• W4200015656 type Work @default.
• W4200015656 citedByCount "0" @default.
• W4200015656 crossrefType "proceedings-article" @default.
• W4200015656 hasAuthorship W4200015656A5012932735 @default.
• W4200015656 hasAuthorship W4200015656A5024915505 @default.
• W4200015656 hasAuthorship W4200015656A5028287372 @default.
• W4200015656 hasAuthorship W4200015656A5030738623 @default.
• W4200015656 hasAuthorship W4200015656A5032271120 @default.
• W4200015656 hasAuthorship W4200015656A5057916077 @default.
• W4200015656 hasAuthorship W4200015656A5081951424 @default.
• W4200015656 hasAuthorship W4200015656A5083071027 @default.
• W4200015656 hasAuthorship W4200015656A5088833390 @default.
• W4200015656 hasConcept C104317684 @default.
• W4200015656 hasConcept C119056186 @default.
• W4200015656 hasConcept C153911025 @default.
• W4200015656 hasConcept C154317977 @default.
• W4200015656 hasConcept C166703698 @default.
• W4200015656 hasConcept C167672396 @default.
• W4200015656 hasConcept C185592680 @default.
• W4200015656 hasConcept C202751555 @default.
• W4200015656 hasConcept C203014093 @default.
• W4200015656 hasConcept C2776090121 @default.
• W4200015656 hasConcept C2779634854 @default.
• W4200015656 hasConcept C41091548 @default.
• W4200015656 hasConcept C502942594 @default.
• W4200015656 hasConcept C553184892 @default.
• W4200015656 hasConcept C55493867 @default.
• W4200015656 hasConcept C62112901 @default.
• W4200015656 hasConcept C67705224 @default.
• W4200015656 hasConcept C74401373 @default.
• W4200015656 hasConcept C86803240 @default.
• W4200015656 hasConcept C8891405 @default.
• W4200015656 hasConcept C95444343 @default.
• W4200015656 hasConceptScore W4200015656C104317684 @default.
• W4200015656 hasConceptScore W4200015656C119056186 @default.
• W4200015656 hasConceptScore W4200015656C153911025 @default.
• W4200015656 hasConceptScore W4200015656C154317977 @default.
• W4200015656 hasConceptScore W4200015656C166703698 @default.
• W4200015656 hasConceptScore W4200015656C167672396 @default.
• W4200015656 hasConceptScore W4200015656C185592680 @default.
• W4200015656 hasConceptScore W4200015656C202751555 @default.
• W4200015656 hasConceptScore W4200015656C203014093 @default.
• W4200015656 hasConceptScore W4200015656C2776090121 @default.
• W4200015656 hasConceptScore W4200015656C2779634854 @default.
• W4200015656 hasConceptScore W4200015656C41091548 @default.
• W4200015656 hasConceptScore W4200015656C502942594 @default.
• W4200015656 hasConceptScore W4200015656C553184892 @default.
• W4200015656 hasConceptScore W4200015656C55493867 @default.
• W4200015656 hasConceptScore W4200015656C62112901 @default.
• W4200015656 hasConceptScore W4200015656C67705224 @default.
• W4200015656 hasConceptScore W4200015656C74401373 @default.
• W4200015656 hasConceptScore W4200015656C86803240 @default.
• W4200015656 hasConceptScore W4200015656C8891405 @default.
• W4200015656 hasConceptScore W4200015656C95444343 @default.
• W4200015656 hasLocation W42000156561 @default.
• W4200015656 hasOpenAccess W4200015656 @default.
• W4200015656 hasPrimaryLocation W42000156561 @default.
• W4200015656 hasRelatedWork W17686375 @default.
• W4200015656 hasRelatedWork W18926617 @default.
• W4200015656 hasRelatedWork W19594259 @default.
• W4200015656 hasRelatedWork W20110034 @default.
• W4200015656 hasRelatedWork W23910689 @default.
• W4200015656 hasRelatedWork W3628815 @default.
• W4200015656 hasRelatedWork W4086413 @default.
• W4200015656 hasRelatedWork W4098668 @default.
• W4200015656 hasRelatedWork W6295290 @default.
• W4200015656 hasRelatedWork W25312611 @default.
• W4200015656 isParatext "false" @default.
• W4200015656 isRetracted "false" @default.
• W4200015656 workType "article" @default.