Targeting cellular double-stranded RNA homeostasis in breast cancer
靶向乳腺癌细胞双链 RNA 稳态
基本信息
- 批准号:10441562
- 负责人:
- 金额:$ 37.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:Antigen PresentationBiologicalBiological AssayBreastBreast Cancer CellCD8-Positive T-LymphocytesCRISPR/Cas technologyCellsChronicCytoplasmDNA DamageDNA MethylationDetectionDouble-Stranded RNAElementsEpigenetic ProcessExhibitsFamilyGene DeletionGene ExpressionGenetically Engineered MouseGenomic InstabilityHomeostasisHumanImmuneImmune signalingImmune systemImmunocompetentImmunologicsImmunomodulatorsImmunotherapeutic agentImmunotherapyInfiltrationInflammationInnate Immune ResponseInterferon Type IInterferonsLeadLinkLuciferasesMHC Class I GenesMalignant NeoplasmsMammary NeoplasmsMammary TumorigenesisMediatingMetastatic breast cancerMitochondriaModificationMolecularMusNormal CellOxidative StressPathway interactionsProductionRNARNA EditingRNA HelicaseRNA ProcessingRegulationReportingRoleSTAT1 geneSignal TransductionSomatic CellSourceSystemTherapeuticTranscriptional Silencer ElementsTumor ImmunityVirus Diseasesanti-PD1 antibodiesanti-canceraspartylglutamatebasecancer cellcancer immunotherapycancer therapycellular targetingconditional knockoutcrosslinking and immunoprecipitation sequencingexperimental studyglutamylalaninehelicasehuman diseaseimmune activationimmune checkpoint blockadeimmunogenicimmunogenicityinhibitorinnate immune sensingknock-downmalignant breast neoplasmmouse modelnew therapeutic targetnoveloverexpressionpathogenpromoterresponsesensorsmall molecule inhibitortherapeutic targettranscriptomicstumortumor growthtumor microenvironmenttumor-immune system interactionstumorigenesis
项目摘要
Summary/Abstract
The immunologically inactive (cold) tumor is a major challenge for effective immunotherapies in many cancers,
including breast cancer. Increasing evidence has demonstrated that human cells express various types of
endogenous double-stranded RNAs (dsRNAs) regardless of pathogen invasion, and aberrant accumulation of
cellular dsRNAs could trigger a detrimental innate immune response in cells. In cancer, these endogenous
immunogenic dsRNAs are suggested as a source of immune induction to increase tumor response to
immunotherapy. However, to exploit the cellular dsRNAs in immunotherapy for cancer, we need to understand
the molecular mechanism for cellular dsRNA homeostasis in normal and malignant cells and find the specific
ways to modulate immunogenic dsRNAs. We found that inhibition of DEAD-box RNA helicase 3X (DDX3X)
resulted in the cytoplasmic accumulation of endogenous dsRNAs in the breast cancer cells. Loss of DDX3X
increased the type I interferon production, STAT1 activation, IFN-stimulated genes (ISGs) expression, and the
MHC class I expression with the enhanced antigen presentation on the breast cancer cells. DDX3X inhibition
also suppressed the tumor growth and increased the tumor infiltration of active CD8+ T cells and DC in the
syngeneic breast cancer mouse model. We hypothesize that inhibiting DDX3X leads to aberrant accumulation
of endogenous dsRNAs, which triggers type I IFN responses and induces an innate immune response in the
tumor. The proposed studies will be focused on understanding the molecular mechanism by which DDX3X
regulates cellular dsRNA homeostasis, providing a link between cellular dsRNAs and immune signals in breast
cancer cells, and establishing novel immunotherapeutic strategies for breast cancer. In Aim 1, we will
determine the molecular mechanism by which DDX3X regulates cellular dsRNAs; In Aim 2, we will study
DDX3X-dsRNAs-Type I IFN axis in cancer cells and human tumor; In Aim 3, we will explore the effect of
inhibiting DDX3X to increase anti-tumor immunity and sensitize tumors to immunotherapy. Our study will reveal
a novel regulatory mechanism of endogenous dsRNAs in cancer and may lead to novel therapeutics targeting
DDX3X for new combinatory immunotherapy.
摘要/摘要
免疫学上无活性(冷)肿瘤是许多癌症有效免疫疗法的主要挑战,
包括乳腺癌。越来越多的证据表明,人类细胞表达了各种类型的
内源性双链RNA(DSRNA),无论病原体入侵如何
细胞DSRNA可能会引发细胞中有害的先天免疫反应。在癌症中,这些内源性
建议将免疫原性DSRNA作为免疫诱导来源,以增加肿瘤对
免疫疗法。但是,要利用免疫疗法中的细胞DSRNA进行癌症,我们需要了解
正常和恶性细胞中细胞DSRNA稳态的分子机制,找到特定
调节免疫原性DSRNA的方法。我们发现抑制死盒RNA解旋酶3X(DDX3X)
导致内源性DSRNA在乳腺癌细胞中的细胞质积累。 DDX3X的损失
增加了I型干扰素产生,STAT1激活,IFN刺激的基因(ISGS)表达和
MHC I类表达具有增强的乳腺癌细胞上的抗原表现。 DDX3X抑制
还抑制了肿瘤的生长并增加了活性CD8+ T细胞和DC的肿瘤浸润
合成性乳腺癌小鼠模型。我们假设抑制DDX3X会导致异常积累
内源性DSRNA,它触发I型IFN反应并诱导先天性免疫反应
瘤。拟议的研究将集中于理解DDX3X的分子机制
调节细胞DSRNA稳态,提供细胞DSRNA和乳房中的免疫信号之间的联系
癌细胞,并为乳腺癌建立新的免疫治疗策略。在AIM 1中,我们将
确定DDX3X调节细胞DSRNA的分子机制;在AIM 2中,我们将学习
癌细胞和人类肿瘤中的DDX3X-DSRNA型I IFN轴;在AIM 3中,我们将探讨
抑制DDX3X以增加抗肿瘤免疫力并使肿瘤对免疫疗法敏感。我们的研究将揭示
内源性DSRNA在癌症中的新型调节机制,可能导致新的治疗剂靶向
新组合免疫疗法的DDX3X。
项目成果
期刊论文数量(0)
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{{ truncateString('Cecil Han', 18)}}的其他基金
Targeting cellular double-stranded RNA homeostasis in breast cancer
靶向乳腺癌细胞双链 RNA 稳态
- 批准号:
10278680 - 财政年份:2021
- 资助金额:
$ 37.38万 - 项目类别:
Targeting cellular double-stranded RNA homeostasis in breast cancer
靶向乳腺癌细胞双链 RNA 稳态
- 批准号:
10674720 - 财政年份:2021
- 资助金额:
$ 37.38万 - 项目类别:
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