Persistent STAT5 signaling in polyfunctional CD4 T cells and its application in adoptive T cell therapy
多功能CD4 T细胞中持续的STAT5信号传导及其在过继性T细胞治疗中的应用
基本信息
- 批准号:10441590
- 负责人:
- 金额:$ 51.23万
- 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:ATAC-seqAntigensBioinformaticsBiological ModelsCAR T cell therapyCD19 geneCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCRISPR/Cas technologyCancer PatientCellsCharacteristicsClustered Regularly Interspaced Short Palindromic RepeatsDataDendritic cell activationEctopic ExpressionEpigenetic ProcessEpitope spreadingEventExposure toFunctional disorderGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGrowthHeterogeneityHistonesHumanIL7 geneImmunologicsImmunotherapyIn VitroInfiltrationInflammatoryInfusion proceduresKnock-outLaboratoriesLymphomaMaintenanceMalignant NeoplasmsMediatingModelingMusPatient-Focused OutcomesPatientsPhenotypePopulationPre-Clinical ModelProcessProductionRelapseReportingResearchResistanceRoleSTAT proteinSignal PathwaySignal TransductionSolidSolid NeoplasmSystemSystems BiologyT cell therapyT-Cell ActivationT-LymphocyteTechnologyTherapeuticTumor ImmunityWorkXenograft ModelXenograft procedureanti-tumor immune responseantitumor effectbasecancer immunotherapychimeric antigen receptorclinical applicationcytokineeffective therapyeffector T cellepigenomicsexhaustexhaustiongenome-widehistone modificationimprovednovel strategiesoverexpressionpre-clinicalpreventprogenitorsingle-cell RNA sequencingtherapy outcometranscriptomicstumortumor growthtumor microenvironment
项目摘要
Project summary/abstract
Recent advances in adoptive T-cell therapy (ACT), especially CD19-targeting chimeric antigen
receptor (CAR) T-cell therapy (CD19CART), have highlighted the potential of immunotherapy to
achieve durable and curative patient outcomes. However, even for the well-developed
CD19CART, many patients have failed to respond to the treatment or succumbed to late relapse.
Moreover, so far ACT in general has not been effective in treating most solid tumors. The major
barriers to effective ACT include deficiencies in donor T cell expansion, persistence and tumor-
infiltration, as well as loss of T-cell effector function - a process termed exhaustion. There is
increasing demand for novel strategies that can overcome these barriers to improve the efficacy
of ACT. The presence of CD4 T cells with a polyfunctional phenotype, characterized by
concomitant production of multiple inflammatory cytokines, has been associated with favorable
therapeutic outcomes in preclinical models and cancer patients. However, how to generate
polyfunctional CD4 (pfCD4) T cells suitable for ACT remains elusive. We previously reported that
CD4 T cells exposed to interleukin 7 (IL7) during antigenic stimulation can acquire
polyfunctionality in a STAT5-dependent manner. Our recent work demonstrated that ectopic
expression of a constitutively active form of STAT5 (CASTAT5) in CD4 T cells induces genome-
wide transcriptional and epigenetic remodeling in tumor-specific CD4 T cells, endowing these
cells polyfunctionality, exhaustion-resistance and tumor-infiltrating capability. Importantly,
CASTAT5 can markedly improve the expansion and persistence of CD19CAR T cells, resulting
in high cure rate in mice with advanced lymphoma. These new findings form the basis of our
central hypothesis that CASTAT5-induced epigenetic remodeling endows CD4 T cells
polyfunctionality and exhaustion-resistance, and these features equip CD4 T cells with superior
helper activities to orchestrate potent antitumor immune responses. This cross-disciplinary multi-
PI project will employ our well-characterized ACT model systems in conjunction with cutting-edge
epigenomics and single cell RNA sequencing technologies to advance our understanding of the
ontogeny, heterogeneity, regulatory circuitry and mechanism of action of pfCD4 T cells.
Specifically, we will investigate how persistent STAT5 signaling induces and maintains pfCD4 T
cells (Aim 1), how CASTAT5-induced pfCD4 T cells potentiate ACT (Aim 2), and the potential
utility of CASTAT5 in human CD19CAR T cells (Aim 3). Successful completion of this project will
establish CASTAT5 as a clinically applicable strategy to overcome the barriers impeding effective
ACT including CAR T cell therapy.
项目概要/摘要
过继性T细胞治疗(ACT)的最新进展,特别是靶向CD 19的嵌合抗原
受体(CAR)T细胞疗法(CD 19 CART),突出了免疫疗法的潜力,
实现持久和治愈性的患者结果。然而,即使是发达国家,
CD 19 CART,许多患者对治疗没有反应或死于晚期复发。
此外,到目前为止,ACT通常在治疗大多数实体瘤方面并不有效。主要
有效ACT的障碍包括供体T细胞扩增、持久性和肿瘤-
浸润,以及T细胞效应器功能的丧失-一个称为耗竭的过程。有
对能够克服这些障碍以提高疗效的新策略的需求日益增加
的ACT。具有多功能表型的CD 4 T细胞的存在,其特征在于
伴随产生多种炎性细胞因子,与有利的
临床前模型和癌症患者的治疗结果。但是,如何生成
适用于ACT的多功能CD 4(pfCD 4)T细胞仍然难以捉摸。我们之前报道过,
在抗原刺激期间暴露于白细胞介素7(IL 7)的CD 4 T细胞可以获得
以STAT 5依赖性方式具有多官能性。我们最近的研究表明,异位
在CD 4 T细胞中STAT 5的组成型活性形式(CASTAT 5)的表达诱导基因组-
广泛的转录和表观遗传重塑肿瘤特异性CD 4 T细胞,赋予这些
细胞的多功能性、抗耗竭性和肿瘤浸润能力。重要的是,
CASTAT 5可以显著改善CD 19 CAR T细胞的扩增和持久性,从而导致CD 19 CAR T细胞的增殖。
在晚期淋巴瘤小鼠中具有高治愈率。这些新发现构成了我们的基础。
CASTAT 5诱导的表观遗传重塑赋予CD 4 T细胞
多功能性和抗耗竭性,这些特征使CD 4 T细胞具有上级
辅助活性以协调有效的抗肿瘤免疫应答。这种跨学科的多-
PI项目将采用我们特征良好的ACT模型系统以及尖端的
表观基因组学和单细胞RNA测序技术,以促进我们对
pfCD 4 T细胞的个体发生、异质性、调节电路和作用机制。
具体来说,我们将研究持续的STAT 5信号传导如何诱导和维持pfCD 4 T细胞的表达。
细胞(目标1),CASTAT 5诱导的pfCD 4 T细胞如何增强ACT(目标2),以及
CASTAT 5在人CD 19 CAR T细胞中的效用(Aim 3)。该项目的成功完成将
将CASTAT 5确立为临床适用的策略,以克服阻碍有效治疗的障碍
ACT包括CAR T细胞疗法。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('HUIDONG SHI', 18)}}的其他基金
Persistent STAT5 signaling in polyfunctional CD4 T cells and its application in adoptive T cell therapy
多功能CD4 T细胞中持续的STAT5信号传导及其在过继性T细胞治疗中的应用
- 批准号:
10317563 - 财政年份:2021
- 资助金额:
$ 51.23万 - 项目类别:
Persistent STAT5 signaling in polyfunctional CD4 T cells and its application in adoptive T cell therapy
多功能CD4 T细胞中持续的STAT5信号传导及其在过继性T细胞治疗中的应用
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慢性淋巴细胞白血病 T 细胞功能障碍的表观遗传调控
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