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.

项目摘要这个多PI的建议，标题为“ SARS-COV-2反应性主题是按照“ RFA-CA-20-039”的回应而写的。健康和癌症中的组织驻留记忆T细胞 SARS-COV-2血清学科学的研究项目。最近的研究表明，随着时间的流逝，对SARS-COV-2感染的抗体反应迅速下降，这意味着缺乏耐用的受保护的体液（B细胞）免疫史。这是否对细胞免疫史也是如此（例如，t 细胞）知之甚少。众所周知，CD8+ TRM细胞是病毒感染的第一道防线在粘膜/障碍物。他们还众所周知，它们可以保护宿主免受同源或异源重新感染。我们的小组是第一个表明TRM细胞是推动有效抗肿瘤免疫反应的关键参与者在肺癌中，TRM细胞是抗PD1疗法的主要细胞靶标。这些关键发现是由于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，生物信息学和癌症的经验免疫学。我们的Multi-Pi团队最近执行了第一台，最大的单细胞RNA-Seq和TCR-Seq 从199例患者中分析SARS-COV-2反应性CD8+和CD4+ T细胞（约300,000个单细胞）。这里，要了解TRM对SARS-COV-2的响应，我们将利用癌症的队列（n = 100）和非关注者（n = 100）将提供超过气道的患者（鼻，口咽，喉），肺和肿瘤组织标本在常规手术期间获得。在AIM 1中，我们将从患有或没有先前的SARS-COV-2感染的癌症和非癌症患者。我们将表演合并气道中CD8+ TRM细胞的单细胞RNA-SEQ和TCR-SEQ分析（鼻，口咽），肺和肿瘤组织。同时，通过使用SARS-COV-2辣椒池刺激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。最近关于非 - 的研究暴露的个体（前CoVID-19大流行）表明先前存在的，循环的CD8+ T细胞，人类冠状病毒交叉反应性。在这里，我们将衡量现有的SARS-COV-2交叉的数量和质量没有先前SARS-COV-2感染的临床或血清学证据的受试者中的反应性TRM反应。在 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。我们将用靶向的胡椒池刺激匹配的PBMC（如上所述）（i）常见的呼吸道RNA病毒（流感（流感），RSV），（ii）持续的DNA病毒（CMV，EBV）和（iii）肿瘤驱动病毒（HPV）定义各个病毒特异性和肿瘤（HPV）特异性CD8+ T细胞的TCR序列；我们将利用TCR 信息以确定粘膜和肿瘤中其他病毒/肿瘤反应性TRM细胞的频率和特性组织细胞。