Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells
NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向
基本信息
- 批准号:9917605
- 负责人:
- 金额:$ 44.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AKT Signaling PathwayBindingBinding ProteinsBinding SitesBloodCell SurvivalCell TherapyCell physiologyCellsCellular StressCellular biologyCellular immunotherapyCitiesClinicCombined Modality TherapyComplexDataDeubiquitinationDevelopmentDiseaseDown-RegulationEducational workshopEffector CellEngineeringEnzymesFOXO1A geneFactor XFoundationsGene ExpressionGene Expression RegulationGenesHaplotypesHomeostasisHumanIFNG geneImmuneImmunityImmunologyImmunotherapyImpairmentIn VitroInfusion proceduresInositolInterferon Type IIInterleukin-15JournalsKLRD1 geneLongevityLymphoidMalignant NeoplasmsMediatingMessenger RNAMolecularMultiple MyelomaMusNatural Killer Cell toxicityNatural Killer CellsNatureNuclear ProteinPathway interactionsPatientsPlayPopulationPre-Clinical ModelProcessProductionProtein SplicingProteinsProto-Oncogene Proteins c-aktPublished CommentPublishingRNA SplicingReportingResistanceRoleSignal PathwaySignal TransductionSignaling ProteinTestingTimeTransforming Growth Factor betaTranslatingTumor-infiltrating immune cellsUbiquitinationVirusWorkXBP1 geneanti-PD-1anti-PD-L1basecancer cellcancer immunotherapeuticscancer immunotherapycancer therapychimeric antigen receptorconditional knockoutcytokinecytotoxicityhuman dataimprovedimproved outcomein vivoinnovationinsightinterleukin-15 receptormigrationneoplastic cellnew therapeutic targetnovelnovel strategiespreventpromoterprotein expressionrecruittraffickingtranscription factortumortumor eradication
项目摘要
NK cells are the first line of defense against tumor cells. We recently developed CAR NK cells for the treatment of
multiple myeloma (MM), which demonstrates improved anti-MM activity. However, challenges still exist for NK cell-
based cancer immunotherapy: some tumor cells are resistant to cytotoxicity of NK cells that have a short life span
after infusion into patients. Thus, further understanding of NK cells will be critical to better harness this population
for immunotherapy. Our data recently published in Nature Immunology show that an important transcription factor,
XBP1s, encoded by an unconventionally spliced mRNA of X-box binding protein (XBP1), positively regulates NK
cell survival and effector functions. XBP1s regulates NK cell cytotoxicity and GZMB gene expression via direct
promoter binding. XBP1s physically interacts with T-BET, a master regulator in NK cells, suggesting that XBP1s
can recruit T-BET to the promoters of target genes. This discovery fills a current gap in the field, as T-BET is known
to positively regulate the expression of GZMB despite lacking direct T-BET binding sites on the GZMB promoter.
Moreover, IL-15, one of the most important cytokines regulating NK cell survival, development, and effector
functions, activates AKT signaling to increase stability of XBP1s protein via deubiquitination, leading to XBP1s
nuclear accumulation. Consistent with these human data, conditional knockout of Xbp1 in mice shows a decreased
number of NK cells and impaired NK cell anti-tumor activity. We believe that we have identified a novel IL-15-AKT-
XBP1s signaling pathway that plays key roles in regulating multiple aspects of NK cell biology. Thus, our overall
hypothesis is that this IL-15-AKT-XBP1s signaling pathway newly identified by our group positively
regulates NK cell survival and effector functions and can be utilized to improve NK cell or CAR NK cell-
based cancer immunotherapy. We propose mechanistic studies regarding how XBP1s regulates NK cell survival
and effector functions. We also propose combinational therapies of IL-15/IL-15Rα with CS1-CAR NK cells or with
B-I09, a novel drug targeting XBP1 splicing to XBP1s that has strong activity in treating various cancers including
MM. IL-15/IL-15Rα can selectively stabilize the XBP1s protein and prevent B-I09-mediated downregulation of
XBP1s and the associated inhibition of functions in NK cells. We will engineer CS1-CAR NK cells to express IL-
15/IL-15Rα or XBP1s to have enhanced in vivo persistence of these cells for continuous tumor eradication. Three
Aims are proposed. Aim 1: Study the mechanism and functional consequences of enhanced XBP1s protein
expression levels via IL-15-AKT signaling in NK cells. Aim 2: Study whether and/or how XBP1s regulates NK cell
survival, proliferation, and trafficking. Aim 3: Study the role of XBP1s in combination therapies of IL-15/IL-15Rα
with a novel drug targeting XPB1s, B-I09, and/or with CS1-CAR NK cells for the treatment of MM. Our project is
significant and timely as IL-15 and IL-15/IL-15Rα are top agents for cancer immunotherapy and are being actively
tested in the clinic. Our studies will lead to new insights into NK cell biology, improve outcomes for NK cell-based
immunotherapy, and facilitate developing innovative cancer immunotherapeutics.
NK 细胞是对抗肿瘤细胞的第一道防线,我们最近开发了用于治疗肿瘤的 CAR NK 细胞。
多发性骨髓瘤 (MM),这表明抗 MM 活性有所改善,但是 NK 细胞仍然存在挑战。
基于癌症免疫疗法:一些肿瘤细胞对寿命较短的 NK 细胞的细胞毒性有抵抗力
因此,进一步了解 NK 细胞对于更好地利用这一群体至关重要。
我们最近发表在《自然免疫学》上的数据表明,一个重要的转录因子,
XBP1s,由 X-box 结合蛋白 (XBP1) 的非常规剪接 mRNA 编码,正向调节 NK
XBP1s 通过直接调节 NK 细胞的细胞毒性和 GZMB 基因表达。
XBP1s 与 NK 细胞中的主要调节因子 T-BET 发生物理相互作用,表明 XBP1s
可以将T-BET招募到目标基因的启动子上,这一发现填补了该领域目前的空白。
尽管 GZMB 启动子上缺乏直接的 T-BET 结合位点,但仍能正向调节 GZMB 的表达。
此外,IL-15是调节NK细胞存活、发育和效应的最重要的细胞因子之一
功能,激活 AKT 信号传导,通过去泛素化提高 XBP1s 蛋白的稳定性,从而产生 XBP1s
与这些人类数据一致,条件性敲除小鼠中的 Xbp1 显示减少。
我们相信我们已经鉴定出一种新型 IL-15-AKT-。
XBP1s 信号通路在调节 NK 细胞生物学的多个方面发挥着关键作用。
假设是我们小组新发现的IL-15-AKT-XBP1s信号通路
调节 NK 细胞存活和效应功能,可用于改善 NK 细胞或 CAR NK 细胞-
我们提出关于 XBP1 如何调节 NK 细胞存活的机制研究。
我们还提出了 IL-15/IL-15Rα 与 CS1-CAR NK 细胞或与 IL-15/IL-15Rα 的联合疗法。
B-I09是一种靶向XBP1剪接至XBP1的新药,在治疗多种癌症方面具有很强的活性,包括
MM. IL-15/IL-15Rα 可以选择性稳定 XBP1s 蛋白并防止 B-I09 介导的下调
XBP1 和相关的 NK 细胞功能抑制 我们将改造 CS1-CAR NK 细胞以表达 IL-。
15/IL-15Rα 或 XBP1 可以增强这些细胞的体内持久性,从而持续根除肿瘤。
提出的目标 1:研究增强的 XBP1s 蛋白的机制和功能后果。
目标 2:研究 XBP1 是否调节 NK 细胞和/或如何调节 NK 细胞。
目标 3:研究 XBP1 在 IL-15/IL-15Rα 联合疗法中的作用。
我们的项目是针对 XPB1s、B-I09 和/或 CS1-CAR NK 细胞的新药治疗 MM。
意义重大且及时,因为 IL-15 和 IL-15/IL-15Rα 是癌症免疫治疗的顶级药物,并且正在积极研究
我们的研究将在临床上进行测试,从而带来对 NK 细胞生物学的新见解,改善基于 NK 细胞的治疗结果。
免疫疗法,并促进开发创新的癌症免疫疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jianhua Yu其他文献
Jianhua Yu的其他文献
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