SARS-CoV-2-reactive tissue-resident memory T cells in healthy and cancer subjects
健康和癌症受试者中的 SARS-CoV-2 反应性组织驻留记忆 T 细胞
基本信息
- 批准号:10688355
- 负责人:
- 金额:$ 73.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-30 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAddressAnimal ModelAntibodiesAntibody ResponseApoptoticAutomobile DrivingB-LymphocytesBioinformaticsBiological AssayBloodCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCOVID-19COVID-19 pandemicCOVID-19 patientCancer PatientCancer Research ProjectCellsCellular ImmunityClinicalCollaborationsCytomegalovirusDNA VirusesDiseaseEconomicsFrequenciesFruitFutureGenerationsGenomicsHead CancerHuman Herpesvirus 4Human PapillomavirusImmuneImmunityImmunologyIndividualInfectionInflammatoryInfluenzaLarynxLinkMalignant NeoplasmsMalignant neoplasm of lungMeasuresMemoryMorbidity - disease rateMucous MembraneNF-kappa BNatureNeck CancerNoseOncogenic VirusesOperative Surgical ProceduresOropharyngealOutcomePathway interactionsPatientsPeptidesPeripheral Blood Mononuclear CellPropertyRNA VirusesReportingResearch Project GrantsRespiratory SystemSARS-CoV-2 infectionScienceSerologySignal TransductionSiteSpecimenStructure of parenchyma of lungT cell receptor repertoire sequencingT cell responseT memory cellT-LymphocyteTimeTissuesTranscriptTumor TissueVaccinesViralVirusVirus Diseasesanti-PD1 therapyanti-tumor immune responseantigen-specific T cellsbasecancer cellcancer typecellular targetingcohortcross reactivitycytotoxicityexhaustexperiencehuman coronavirusinsightmortalitymouse modelmucosal sitenovel therapeuticspandemic diseasepatient subsetspost SARS-CoV-2 infectionrecruitrespiratoryresponsesevere COVID-19single-cell RNA sequencingtranscriptometranscriptomicstumortumor immunology
项目摘要
PROJECT SUMMARY
This multi-PI proposal titled “SARS-CoV-2-reactive
subjects” is written in response to ‘RFA-CA-20-039’ -
tissue-resident memory T cells in healthy and cancer
Research projects in SARS-CoV-2 Serological Sciences.
Recent studies have shown that antibody responses to SARS-CoV-2 infection decline rapidly over time, implying
a lack of durable protective humoral (B cell) immunity. Whether this is also true for cellular immunity (e.g., T
cells) is poorly understood. It is well established that CD8+ TRM cells are the first line of defense in viral infections
at mucosal/barrier sites. They are also known to protect hosts against homologous or heterologous re-infections.
Our group was the first to show that TRM cells are pivotal players in driving effective anti-tumor immune responses
in lung cancer, and that TRM cells are the primary cellular targets of anti-PD1 therapies. These key findings were
possible because of the ongoing collaboration between Dr. Vijayanand, Dr. Ay, and Dr. Ottensmeier (Multi-PI).
This team brings together experience in T cell immunology, single-cell genomics, bioinformatics, and cancer
immunology. Our Multi-PI team has recently performed the first and largest single-cell RNA-seq and TCR-seq
analysis of SARS-CoV-2-reactive CD8+ and CD4+ T cells (~300,000 single-cells) from COVID-19 patients. Here,
to understand TRM responses to SARS-CoV-2, we will capitalize on a cohort of cancer (n=100) and non-cancer
(n=100) patients, who will provide excess airway (nasal, oropharynx, larynx), lung and tumor tissue specimens
obtained during routine surgery. In AIM 1, we will define the properties of SARS-CoV-2 reactive TRM cells from
cancer and non-cancer patients with or without previous SARS-CoV-2 infection. We will perform combined
single-cell RNA-seq and TCR-seq analysis of CD8+ TRM cells in the airways (nasal, oropharynx), lung, and tumor
tissue. In parallel, by stimulating PBMCs with SARS-CoV-2 peptide pool, we will determine the transcriptomic
and TCR sequence of SARS-CoV-2 reactive T cells. We will utilize this TCR sequence information to define the
numbers and properties of SARS-CoV-2 reactive-TRM cells in mucosal and tumor tissues. Recent studies in non-
exposed individuals (pre-COVID-19 pandemic) indicate pre-existing, circulating CD8+ T cells, with human
coronavirus cross-reactivity. Here, we will measure the quantity and quality of pre-existing SARS-CoV-2 cross-
reactive TRM responses in subjects without clinical or serological evidence of previous SARS-CoV-2 infection. In
AIM 2, we will assess the impact of SARS-CoV-2 infection on anti-tumor and other anti-viral TRM responses. We
will stimulate matched PBMCs (as above) with peptide pools targeting (i) common respiratory RNA viruses
(influenza (FLU), RSV), (ii) persistent DNA viruses (CMV, EBV), and (iii) a tumor-driving virus (HPV) to define
the TCR sequence of the respective virus-specific and tumor(HPV)-specific CD8+ T cells; we will utilize the TCR
information to determine frequency and properties of other virus/tumor-reactive TRM cells in mucosal and tumor-
tissue cells.
项目摘要
这个多PI提案题为“SARS-CoV-2-reactive
受试者”是针对“RFA-CA-20-039”编写的-
健康和癌症中的组织驻留记忆T细胞
SARS-CoV-2血清学研究项目。
最近的研究表明,对SARS-CoV-2感染的抗体应答随时间迅速下降,这意味着
缺乏持久的保护性体液(B细胞)免疫。这是否也适用于细胞免疫(例如,不
细胞)知之甚少。已经确定,CD 8 + TRM细胞是病毒感染的第一道防线
在粘膜/屏障部位。它们还已知可保护宿主免受同源或异源再感染。
我们的研究小组是第一个证明TRM细胞在驱动有效的抗肿瘤免疫反应中起关键作用的人。
TRM细胞是抗PD 1治疗的主要细胞靶点。这些主要发现是
这是因为Vijayanand博士、Ay博士和Ottensmeier博士(多PI)之间正在进行的合作。
该团队汇集了T细胞免疫学、单细胞基因组学、生物信息学和癌症方面的经验
免疫学我们的Multi-PI团队最近进行了第一个也是最大的单细胞RNA-seq和TCR-seq
分析来自COVID-19患者的SARS-CoV-2反应性CD 8+和CD 4 + T细胞(约30万个单细胞)。在这里,
为了了解TRM对SARS-CoV-2的反应,我们将利用癌症(n=100)和非癌症队列
(n=100)例患者,将提供过量气道(鼻、口咽、喉)、肺和肿瘤组织标本
在常规手术中获得。在AIM 1中,我们将定义SARS-CoV-2反应性TRM细胞的特性,
有或无SARS-CoV-2感染史的癌症和非癌症患者。我们将结合
气道(鼻、口咽)、肺和肿瘤中CD 8 + TRM细胞的单细胞RNA-seq和TCR-seq分析
组织.同时,通过用SARS-CoV-2肽库刺激PBMC,我们将确定转录组学,
和SARS-CoV-2反应性T细胞的TCR序列。我们将利用该TCR序列信息来定义
粘膜和肿瘤组织中SARS-CoV-2反应性TRM细胞的数量和性质。最近的研究在非
暴露个体(COVID-19大流行前)表明预先存在的循环CD 8 + T细胞,
冠状病毒交叉反应性。在这里,我们将测量预先存在的SARS-CoV-2交叉感染的数量和质量,
无既往SARS-CoV-2感染临床或血清学证据的受试者的反应性TRM应答。在
目的2,我们将评估SARS-CoV-2感染对抗肿瘤和其他抗病毒TRM反应的影响。我们
将用靶向(i)常见呼吸道RNA病毒的肽库刺激匹配的PBMC(如上所述
(流感病毒(FLU)、RSV),(ii)持久性DNA病毒(CMV、EBV),和(iii)肿瘤驱动病毒(HPV),以定义
相应的病毒特异性和肿瘤(HPV)特异性CD 8 + T细胞的TCR序列;我们将利用TCR序列
确定粘膜和肿瘤中其他病毒/肿瘤反应性TRM细胞的频率和特性的信息-
组织细胞
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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Ferhat Ay其他文献
Ferhat Ay的其他文献
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{{ truncateString('Ferhat Ay', 18)}}的其他基金
Using Common Fund datasets for prioritization of disease-associated genetic variants
使用共同基金数据集对与疾病相关的遗传变异进行优先排序
- 批准号:
10585864 - 财政年份:2022
- 资助金额:
$ 73.24万 - 项目类别:
SARS-CoV-2-reactive tissue-resident memory T cells in healthy and cancer subjects
健康和癌症受试者中的 SARS-CoV-2 反应性组织驻留记忆 T 细胞
- 批准号:
10222422 - 财政年份:2020
- 资助金额:
$ 73.24万 - 项目类别:
SARS-CoV-2-reactive tissue-resident memory T cells in healthy and cancer subjects
健康和癌症受试者中的 SARS-CoV-2 反应性组织驻留记忆 T 细胞
- 批准号:
10855009 - 财政年份:2020
- 资助金额:
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Defining interaction quantitative trait loci (iQTLs) in the human genome
定义人类基因组中的相互作用数量性状位点 (iQTL)
- 批准号:
9980439 - 财政年份:2018
- 资助金额:
$ 73.24万 - 项目类别:
Defining interaction quantitative trait loci (iQTLs) in the human genome
定义人类基因组中的相互作用数量性状位点 (iQTL)
- 批准号:
9576241 - 财政年份:2018
- 资助金额:
$ 73.24万 - 项目类别:
Studying the function of human genetic variation in the light of 3D genome organization
根据 3D 基因组组织研究人类遗传变异的功能
- 批准号:
10624054 - 财政年份:2018
- 资助金额:
$ 73.24万 - 项目类别:
Defining interaction quantitative trait loci (iQTLs) in the human genome
定义人类基因组中的相互作用数量性状位点 (iQTL)
- 批准号:
10603644 - 财政年份:2018
- 资助金额:
$ 73.24万 - 项目类别:
Defining interaction quantitative trait loci (iQTLs) in the human genome
定义人类基因组中的相互作用数量性状位点 (iQTL)
- 批准号:
9751340 - 财政年份:2018
- 资助金额:
$ 73.24万 - 项目类别:
Defining interaction quantitative trait loci (iQTLs) in the human genome
定义人类基因组中的相互作用数量性状位点 (iQTL)
- 批准号:
10226063 - 财政年份:2018
- 资助金额:
$ 73.24万 - 项目类别:
Defining interaction quantitative trait loci (iQTLs) in the human genome
定义人类基因组中的相互作用数量性状位点 (iQTL)
- 批准号:
10457906 - 财政年份:2018
- 资助金额:
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