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：
10222422
负责人：
Ferhat Ay
金额：
$ 144.63万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222422
关键词：
2019-nCoV Address Antibodies Antibody Response Antiviral Agents Apoptotic Automobile Driving B-Lymphocytes Bioinformatics Biological Assay Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene COVID-19 COVID-19 pandemic Cancer Patient Cancer Research Project Cells Cellular Immunity Clinical Collaborations Cytomegalovirus DNA Viruses Disease Economics Frequencies Fruit Future Generations Genomics Head Cancer Human Herpesvirus 4 Human Papillomavirus Immune Immunity Immunology Individual Infection Inflammatory Influenza Larynx Link Malignant Neoplasms Malignant neoplasm of lung Measures Memory Modeling Morbidity - disease rate Mucous Membrane NF-kappa B Nature Neck Cancer Nose Oncogenic Viruses Operative Surgical Procedures Oropharyngeal Outcome Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Property RNA Viruses Reporting Research Project Grants Respiratory System Science Serological Signal Transduction Site Specimen Structure of parenchyma of lung T cell response T memory cell T-Lymphocyte Time Tissues Transcript Tumor Tissue Vaccines Virus Virus Diseases anti-PD1 therapy anti-tumor immune response antigen-specific T cells base cancer cell cellular targeting cohort coronavirus disease cross reactivity cytotoxicity exhaust experience human coronavirus insight mortality mouse model mucosal site novel therapeutics pandemic disease patient subsets recruit respiratory response single-cell RNA sequencing transcriptome transcriptomics tumor tumor 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.

项目概要这项多 PI 提案名为“SARS-CoV-2-reactive 主题”是为了回应“RFA-CA-20-039”而写的 - 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，针对 SARS-CoV-2 感染的抗体反应随着时间的推移迅速下降，这意味着缺乏持久的保护性体液（B 细胞）免疫是否也适用于细胞免疫（例如 T 细胞）。人们对 CD8+ TRM 细胞是病毒感染的第一道防线知之甚少。还已知它们可以保护宿主免受同源或异源再感染。我们的团队率先证明 TRM 细胞是驱动有效抗肿瘤免疫反应的关键因素在肺癌中，TRM 细胞是抗 PD1 疗法的主要细胞靶标。之所以可能，是因为 Vijayanand 博士、Ay 博士和 Ottensmeier 博士（Multi-PI）之间的持续合作。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我们的 Multi-PI 团队最近进行了第一个也是最大的单细胞 RNA 测序和 TCR 测序。对来自 COVID-19 患者的 SARS-CoV-2 反应性 CD8+ 和 CD4+ T 细胞（约 300,000 个单细胞）进行分析。为了了解 TRM 对 SARS-CoV-2 的反应，我们将利用一组癌症 (n=100) 和非癌症 (n=100)名患者，将提供多余的气道（鼻、口咽、喉）、肺和肿瘤组织标本在 AIM 1 中，我们将定义来自常规手术期间获得的 SARS-CoV-2 反应性 TRM 细胞的特性。既往感染过 SARS-CoV-2 的癌症患者和非癌症患者，我们将进行联合治疗。对气道（鼻、口咽）、肺和肿瘤中 CD8+ TRM 细胞进行单细胞 RNA-seq 和 TCR-seq 分析同时，通过用 SARS-CoV-2 肽库刺激 PBMC，我们将确定转录组。 SARS-CoV-2 反应性 T 细胞的 TCR 序列我们将利用此 TCR 序列信息来定义粘膜和肿瘤组织中 SARS-CoV-2 反应性 TRM 细胞的数量和特性。暴露的个体（COVID-19 大流行前）表明预先存在循环 CD8+ T 细胞，与人类在这里，我们将测量预先存在的 SARS-CoV-2 交叉反应的数量和质量。没有既往 SARS-CoV-2 感染的临床或血清学证据的受试者的反应性 TRM 反应。 AIM 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。将用针对 (i) 常见呼吸道 RNA 病毒的肽池刺激匹配的 PBMC（如上所述）（流感 (FLU)、RSV）、(ii) 持久性 DNA 病毒（CMV、EBV）和 (iii) 肿瘤驱动病毒 (HPV) 来定义我们将利用 TCR 各自的病毒特异性和肿瘤 (HPV) 特异性 CD8+ T 细胞的 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。