Role and Regulation of NKG2D Ligand Expression on Tumor-Infiltrating Myeloid Cells
NKG2D 配体表达对肿瘤浸润骨髓细胞的作用和调节
基本信息
- 批准号:9252223
- 负责人:
- 金额:$ 3.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAnimalsAntibodiesAreaBindingBlocking AntibodiesCSF1 geneCancer PatientCell Surface ReceptorsCell physiologyCellsClinicalCytoplasmic GranulesDataFamilyGenesGeneticGrowthHumanImmuneImmune responseImmune systemImmunologic MonitoringImmunotherapyIn VitroIncidenceInjectableInterruptionKnock-outKnockout MiceLaboratoriesLentivirus VectorLigandsLymphocyteMalignant NeoplasmsMediatingModelingMolecularMonitorMusMyelogenousMyeloid CellsNatural Killer CellsNormal CellNormal tissue morphologyPIK3CG genePathway interactionsPatientsProteinsPublishingRegulationResearchResearch Project GrantsRoleSignal PathwaySignal TransductionSourceSpecificityStressT-LymphocyteTP53 geneTestingTherapeuticTransplantationTumor-Derivedanticancer researchbasecancer cellcancer therapycell killingcell transformationcellular engineeringclinical developmentcytokinecytokine therapycytotoxicdesensitizationhumanized mouseimprovedin vivoinhibitor/antagonistkillingsknock-downmacrophagemelanomamonocytemortalitymouse modelneoplastic cellnovelnovel therapeuticsoverexpressionperipheral bloodpreventpublic health relevancereceptorresponsesarcomatargeted cancer therapytherapeutic targettumortumor growthtumorigenesis
项目摘要
DESCRIPTION (provided by applicant): Treatments that activate immune responses against tumor cells have revolutionized cancer therapeutics. These treatments are the culmination of decades of studies into how the immune system recognizes and eliminates cancer, but more research is necessary to find additional therapeutic targets and improve current ones. Natural Killer (NK) cells are one type of immune cell with potent anti-tumor activities. NK cells delineate
cancer cells from normal tissue using germline-encoded cell surface receptors that recognize molecules on transformed cells but not healthy cells. NK cells eliminate tumors by secreting cytotoxic granules and powerful anti-tumor cytokines. Because many therapies to boost NK responses are in clinical development, it is crucial to thoroughly explore the mechanisms that regulate NK activity against tumors. A recent study in our laboratory provided evidence that tumor-infiltrating myeloid cells persistently stimulate NK cells through the NK immunoreceptor NKG2D. This persistent stimulation causes NK cells to be less active and unable to kill cancer cells, allowing the tumor to evade NK recognition. This desensitization is driven by the NKG2D ligand (NKG2D-L) RAE-1δ expressed on tumor-infiltrating macrophages and monocytes. Preliminary data suggest that myeloid RAE-1δ expression is caused by the cytokine MCSF, produced by tumor cells. Thus, tumors may facilitate their own growth using a multicellular axis to circumvent NK cell-mediated immunosurveillance. This application seeks to further explore the molecular underpinnings of these findings, and to test whether interrupting NKG2D/RAE-1δ interactions between NK cells and myeloid cells can relieve this desensitization and promote tumor rejection. In Aim 1, blocking antibodies against MCSF, lentiviral overexpression of MCSF, and Cas9-mediated knockout of the MCSF gene in tumor cells will be used to determine whether tumor-derived MCSF promotes RAE-1δ expression on tumor-infiltrating myeloid cells in transplanted and autochthonous tumor models. The signaling pathways responsible for RAE-1δ induction by MCSF will be explored by examining whether PI3K, downstream of MCSF stimulation, regulates RAE-1δ in macrophages. Overexpression and knock-down strategies will be used to modulate PI3K signals to examine the contribution of this pathway to RAE-1δ induction. Finally, I will determine whether human MCSF can stimulate NKG2D-L induction on peripheral blood monocytes, and examine human NKG2D-L expression on myeloid cells infiltrating tumors in humanized mice. In Aim 2, blocking antibodies against MCSF and RAE-1δ, genetic ablation of RAE-1δ, and macrophage depletion will be used to determine whether interrupting the MCSF/RAE-1δ/NKG2D desensitization axis, alone or in combination with other therapies that activate NK cells, can promote rejection of tumors expressing ligands for NKG2D and other NK receptors. We hypothesize that MCSF- and RAE-1δ-dependent NK desensitization is a common feature of tumors and a potentially worthwhile target for cancer therapy.
描述(由申请人提供):激活针对肿瘤细胞的免疫应答的治疗已经彻底改变了癌症治疗方法。这些治疗方法是数十年来研究免疫系统如何识别和消除癌症的结果,但还需要更多的研究来寻找其他治疗靶点并改善当前的治疗靶点。自然杀伤(NK)细胞是一种具有强效抗肿瘤活性的免疫细胞。NK细胞描绘
利用生殖细胞编码的细胞表面受体从正常组织中分离出癌细胞,该受体识别转化细胞上的分子,但不识别健康细胞。NK细胞通过分泌细胞毒性颗粒和强大的抗肿瘤细胞因子来消除肿瘤。由于许多增强NK反应的疗法正在临床开发中,因此彻底探索调节NK活性对抗肿瘤的机制至关重要。 我们实验室最近的一项研究提供的证据表明,肿瘤浸润性骨髓细胞通过NK免疫受体NKG 2D持续刺激NK细胞。这种持续的刺激导致NK细胞活性降低,无法杀死癌细胞,从而使肿瘤逃避NK识别。这种脱敏是由肿瘤浸润性巨噬细胞和单核细胞上表达的NKG 2D配体(NKG 2D-L)RAE-1δ驱动的。初步数据表明,髓系RAE-1δ表达是由肿瘤细胞产生的细胞因子MCSF引起的。因此,肿瘤可以利用多细胞轴来规避NK细胞介导的免疫监视,从而促进其自身的生长。本申请旨在进一步探索这些发现的分子基础,并测试中断NK细胞和骨髓细胞之间的NKG 2D/RAE-1δ相互作用是否可以缓解这种脱敏并促进肿瘤排斥。 在目标1中,将使用针对MCSF的阻断抗体、MCSF的慢病毒过表达和肿瘤细胞中的Cas9介导的MCSF基因敲除来确定肿瘤来源的MCSF是否促进移植和自体肿瘤模型中的肿瘤浸润性骨髓细胞上的RAE-1δ表达。将通过检查MCSF刺激下游的PI 3 K是否调节巨噬细胞中的RAE-1δ来探索负责MCSF诱导RAE-1 δ的信号传导途径。将使用过表达和敲低策略来调节PI 3 K信号,以检查该途径对RAE-1δ诱导的贡献。最后,我将确定人MCSF是否可以刺激外周血单核细胞上的NKG 2D-L诱导,并检查人源化小鼠中骨髓细胞浸润肿瘤上的人NKG 2D-L表达。 在目标2中,将使用针对MCSF和RAE-1δ的阻断抗体、RAE-1δ的基因消融和巨噬细胞耗竭来确定单独或与其他激活NK细胞的疗法联合中断MCSF/RAE-1δ/NKG 2D脱敏轴是否可以促进表达NKG 2D配体和其他NK受体的肿瘤的排斥。我们假设MCSF和RAE-1δ依赖性NK脱敏是肿瘤的一个共同特征,也是一个潜在的有价值的癌症治疗靶点。
项目成果
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