KIR2DL2 Immune Checkpoint as Modulator of T-Cell Effector Function
KIR2DL2 免疫检查点作为 T 细胞效应器功能的调节器
基本信息
- 批准号:10649989
- 负责人:
- 金额:$ 19.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAdoptive ImmunotherapyAnimal ModelAutoimmunityBindingBiologicalBiological AssayBiologyCD8-Positive T-LymphocytesCD8B1 geneCell CommunicationCell Death InductionCellsCellular biologyClinicalClonal ExpansionClustered Regularly Interspaced Short Palindromic RepeatsConditioned ReflexDataDockingEducationElementsEventGeneral PopulationGenesGeneticGenetic TranscriptionGenomicsGoalsHLA-C AntigensHumanITIMImmuneImmunoglobulinsImmunologic SurveillanceImmunoprecipitationImmunotherapyImpairmentInfusion proceduresInterferon Type IIKiller CellsKnowledge acquisitionLigandsLinkLiquid substanceLymphocyteMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMediatingMemoryMethodsModelingModificationMolecularMolecular Mechanisms of ActionNatural Killer CellsOutcomePTPN6 genePathway interactionsPatient observationPatientsPerformancePre-Clinical ModelProteomicsProtocols documentationResearchRoleShapesSignal PathwaySignal TransductionSolidSolid NeoplasmT cell therapyT-Cell ActivationT-Cell ReceptorT-LymphocyteTestingTherapeuticTimeTransgenic OrganismsTyrosineUp-RegulationVirus DiseasesWestern BlottingXenograft Modelchimeric antigen receptorchimeric antigen receptor T cellscytokinecytotoxicdesigneffector T cellengineered T cellsgenome editingimmune cell checkpointsimmune checkpointimprovedin vivokiller immunoglobulin-like receptormanufacturemelanomamouse modelmutantneoplastic cellnoveloverexpressionpancreatic cancer modelpharmacologicpreventreceptorreceptor bindingreceptor expressiontranslational potentialtumortumor growthγδ T cells
项目摘要
Project Summary
Killer cell immunoglobulin-like receptors (KIR) are mainly expressed by NK cells, although their
expression has also been described in CD4+, CD8+ and γδ T cells. Within CD8 T cells, KIR expression is
induced at later stages of lymphocyte maturation and is thought to regulate specific T cell effector functions.
Within KIR receptors, KIR2DL2 modulates T cell effector functions, as KIR2DL2+ CD8+ T cells present
reduced level of activation-induced cell death, and poor IFN-γ secretion after T cell receptor (TCR)
stimulation. The notion of a suppressive function of KIR2DL2 expression in CD8+ T cells is supported by the
observation that patients that express its cognate ligand, HLA-C1, showed decreased overall survival and
could not control tumor growth. Our preliminary data show that KIR2DL2 expression increases in vivo in
adoptively transferred T cells in patients and in preclinical models of adoptive immunotherapy. Using a
pancreatic tumor model, we found that chimeric antigen receptor (CAR)-T cells expressing KIR2DL2 were
significantly less cytotoxic than their KIR2DL2- counterparts in presence of KIR2DL2’s ligand. Furthermore,
KIR2DL2 expression in CAR-T cells was associated with reduced antitumor efficacy, in an HLA-I-dependent
manner, in a murine model of pancreatic cancer. Based on these preliminary findings we hypothesize that
KIR2DL2 behaves as a T cell immune checkpoint, modulating T cell effector function and leading to
an ineffective immunosurveillance. Therefore, targeting KIR2DL2 during T cell manufacturing may
improve T cell performance after cell infusion. We will test our hypothesis by 1) Defining the modulatory
mechanisms whereby KIR2DL2 shapes CAR- and TCR-transgenic T cell antitumoral effector function. We
will determine the overall effect of KIR2DL2 engagement in TCR-transgenic and CAR-T cell effector function.
Additionally, we will determine which regions within KIR2DL2 are responsible for its modulatory function.
Finally, we will characterize both the KIR2DL2 signaling interactome and the downstream events triggered
by its ligand interaction by immunoprecipitation and proteomic analyses. 2) Improving T cell performance for
the enhancement of adoptive cell immunotherapies (ACTs) by abrogating KIR2DL2 function. To prevent its
inhibitory effect, manipulation of KIR2DL2 expression and/or signaling will be conducted and adapted to the
current protocols for CAR-T cell manufacturing. Based on the anticipated results, we will link for the first time
the biological and molecular function of KIR2DL2 within therapeutic T cells. The proposed studies will
increase our mechanistic understanding of KIR2DL2 biology and will generate novel cell products with high
translational potential.
项目概要
杀伤细胞免疫球蛋白样受体(KIR)主要由 NK 细胞表达,尽管它们
CD4+、CD8+ 和 γδ T 细胞中也有表达。在 CD8 T 细胞内,KIR 表达为
在淋巴细胞成熟的后期诱导,被认为可以调节特定的 T 细胞效应功能。
在 KIR 受体内,KIR2DL2 调节 T 细胞效应功能,因为 KIR2DL2+ CD8+ T 细胞存在
T 细胞受体 (TCR) 后激活诱导的细胞死亡水平降低,IFN-γ 分泌不良
刺激。 CD8+ T 细胞中 KIR2DL2 表达的抑制功能的概念得到以下支持:
观察到表达其同源配体 HLA-C1 的患者表现出总体生存率下降,并且
无法控制肿瘤的生长。我们的初步数据表明,KIR2DL2 表达在体内增加
在患者和过继免疫治疗的临床前模型中过继转移 T 细胞。使用
胰腺肿瘤模型中,我们发现表达 KIR2DL2 的嵌合抗原受体 (CAR)-T 细胞
在 KIR2DL2 配体存在的情况下,其细胞毒性明显低于其 KIR2DL2- 对应物。此外,
在 HLA-I 依赖性的研究中,CAR-T 细胞中的 KIR2DL2 表达与抗肿瘤功效降低相关
方式,在小鼠胰腺癌模型中。根据这些初步发现,我们假设
KIR2DL2 充当 T 细胞免疫检查点,调节 T 细胞效应功能并导致
无效的免疫监视。因此,在 T 细胞制造过程中靶向 KIR2DL2 可能
提高细胞输注后 T 细胞的性能。我们将通过 1)定义调节来检验我们的假设
KIR2DL2 塑造 CAR 和 TCR 转基因 T 细胞抗肿瘤效应功能的机制。我们
将确定 KIR2DL2 参与 TCR 转基因和 CAR-T 细胞效应功能的总体效果。
此外,我们将确定 KIR2DL2 内的哪些区域负责其调节功能。
最后,我们将描述 KIR2DL2 信号相互作用组和触发的下游事件
通过免疫沉淀和蛋白质组分析通过其配体相互作用。 2) 提高T细胞性能
通过废除 KIR2DL2 功能来增强过继性细胞免疫疗法 (ACT)。为防止其
将进行 KIR2DL2 表达和/或信号传导的抑制作用、操纵并适应
CAR-T 细胞制造的现行协议。根据预期结果,我们将第一时间进行链接
KIR2DL2 在治疗性 T 细胞中的生物学和分子功能。拟议的研究将
增加我们对 KIR2DL2 生物学机制的理解,并将产生具有高活性的新型细胞产品
翻译潜力。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Daniel Abate-Daga其他文献
Daniel Abate-Daga的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Daniel Abate-Daga', 18)}}的其他基金
Understanding the influence of bone-metastatic prostate cancer and mesenchymal stromal cells on γδ T cells, in the bone microenvironment.
了解骨微环境中骨转移性前列腺癌和间充质基质细胞对 γT 细胞的影响。
- 批准号:
10578810 - 财政年份:2020
- 资助金额:
$ 19.69万 - 项目类别:
Understanding the influence of bone-metastatic prostate cancer and mesenchymal stromal cells on γδ T cells, in the bone microenvironment.
了解骨微环境中骨转移性前列腺癌和间充质基质细胞对 γT 细胞的影响。
- 批准号:
10356098 - 财政年份:2020
- 资助金额:
$ 19.69万 - 项目类别:
相似海外基金
VLA-4–targeted 67Cu-LLP2A preconditioning enhances efficacy of T-cell-based adoptive immunotherapy
VLA-4™ 靶向 67Cu-LLP2A 预处理增强基于 T 细胞的过继免疫疗法的疗效
- 批准号:
10713034 - 财政年份:2023
- 资助金额:
$ 19.69万 - 项目类别:
Phase I first-in-human trial for ThINKK adoptive immunotherapy in children with high-risk cancers
针对高危癌症儿童的ThINKK过继免疫疗法的I期首次人体试验
- 批准号:
484371 - 财政年份:2023
- 资助金额:
$ 19.69万 - 项目类别:
Operating Grants
Phase I first-in-human trial of ThINKK adoptive immunotherapy in children with high-risk cancers
针对高危癌症儿童的ThINKK过继免疫疗法的I期首次人体试验
- 批准号:
473376 - 财政年份:2022
- 资助金额:
$ 19.69万 - 项目类别:
Operating Grants
Development of Adoptive Immunotherapy Focusing on Follicular Helper T Cell Biology
专注于滤泡辅助 T 细胞生物学的过继免疫疗法的发展
- 批准号:
21K16420 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Mathematical Model-Guided Adoptive Immunotherapy in Bladder Cancer
数学模型引导的膀胱癌过继免疫治疗
- 批准号:
10180117 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
Mathematical Model-Guided Adoptive Immunotherapy in Bladder Cancer
数学模型引导的膀胱癌过继免疫治疗
- 批准号:
10364687 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
Mathematical Model-Guided Adoptive Immunotherapy in Bladder Cancer
数学模型引导的膀胱癌过继免疫治疗
- 批准号:
10599851 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
Elucidation of the function of the new NK cell subset and its application to adoptive immunotherapy
阐明新NK细胞亚群的功能及其在过继性免疫治疗中的应用
- 批准号:
21H04832 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Development of a combinatorial approach of antibody therapeutics and adoptive immunotherapy for cancer
开发抗体疗法和癌症过继免疫疗法的组合方法
- 批准号:
21K19422 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Adoptive immunotherapy for adult T-cell leukemia/lymphoma with ex vivo expanded multi-tumor associated antigen specific cytotoxic T-cells
使用离体扩增的多肿瘤相关抗原特异性细胞毒性 T 细胞对成人 T 细胞白血病/淋巴瘤进行过继免疫治疗
- 批准号:
20K17375 - 财政年份:2020
- 资助金额:
$ 19.69万 - 项目类别:
Grant-in-Aid for Early-Career Scientists