Project 2: Susceptibility of Lung Cancer Cells to SARS- CoV-2 Infection and Antibody-Mediated Neutralization

项目2：肺癌细胞对SARS-CoV-2感染的易感性和抗体介导的中和作用

• 批准号: 10222310
• 负责人: Adolfo Garcia-Sastre
• 金额: $ 87.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10222310
• 关键词: 2019-nCoV; Address; Age; Antibodies; Antiviral Agents; Bioinformatics; Biological Assay; COVID-19; COVID-19 pandemic; Cancer Patient; Cells; Clinical; Clinical Sciences; Clinical Trials; Collaborations; Collection; Data; Data Science Core; Data Set; Defect; Development; Disease; Emergency Situation; Epithelial; Epithelial Cells; Epithelium; Evaluation; Exhibits; Exposure to; Future; Genetic Transcription; Genomic approach; Histology; Human; Immune; Immune Sera; Immune response; Individual; Infection; Influenza A virus; Interferons; Kidney; Knowledge; Lung; Lung Neoplasms; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methods; Molecular; Monitor; Monkeys; Natural Immunity; Normal Cell; Normal tissue morphology; Patients; Pharmaceutical Preparations; Population; Predisposition; Preparation; Prevention strategy; Production; Proteins; Resistance; Resources; Risk; Sample Size; Sampling; Serological; Smoking; Smoking Status; Specificity; Structure of respiratory epithelium; Sum; Tissues; Tobacco smoking behavior; Vaccination; Vaccines; Viral; Virus Diseases; Virus Receptors; Virus Replication; acquired immunity; adaptive immunity; antibody-dependent cell cytotoxicity; antiviral immunity; base; cancer cell; cohort; comorbidity; cytokine; demographics; experimental study; gender diversity; individual patient; individual variation; influenzavirus; insight; inter-individual variation; molecular subtypes; mortality; multidisciplinary; neoplastic cell; neutralizing antibody; novel therapeutic intervention; pandemic influenza; patient population; permissiveness; pre-clinical; prevent; protective efficacy; protein expression; receptor; remdesivir; respiratory; respiratory virus; response; screening panel; single-cell RNA sequencing; transcriptomics; tumor; virology

PROJECT 2: ABSTRACT Project 2 is based on evidence that lung cancer patients have higher susceptibility to SARS-CoV-2 infection and increased risk of severe disease and mortality. This increased vulnerability is likely due to a combination of factors, including immune-suppressing effects of the cancer itself or its treatment, age, pre-existing comorbidities, or smoking. Moreover, the potential elevated levels of the receptor for SARS-CoV-2, ACE2 protein, in tumor and tumor-adjacent normal tissues observed in cancer patients and in lungs of tobacco smoking individuals likely contributes to the susceptibility of these patients to SARS-CoV-2. Tumor cells are also known to be more permissive to viral replication due to defects in innate antiviral immunity. The potential for increased SARS-CoV-2 amplification in lung cancer cells might be a major factor contributing to enhanced COVID-19 disease in lung cancer patients. An increased susceptibility to viral infection and replication in lung cells in these patients might also impact the ability of neutralizing antibodies to block viral replication, making lung cancer patients more susceptible to SARS-CoV-2 infection and less able to become immune. Thus, a better understanding of the factors that impact SARS-CoV-2 replication in lung cancer and normal lung cells is needed for devising strategies to reduce the risk of lung cancer patients for severe COVID-19 disease, and for evaluation of the protective efficacy of future SARS-CoV-2 vaccines in these patients. To address these knowledge gaps, in Aim 1 we will identify factors associated with the inter-individual variation in susceptibility to infection by SARS- CoV-2 using an existing unique panel of human lung derived cancer and normal epithelial cells, and relate these factors to key clinical, demographic, and molecular features. We will use a combination of virological and genomics approaches, transcriptomics, and scRNAseq assays. The specificity of the susceptibility to SARS- CoV-2 infection will be evaluated by comparison to other respiratory viruses, such as influenza viruses. In Aim 2, we will characterize the functional activity of antibodies and antivirals in susceptible lung cancer and normal lung epithelial cells. Together with Project 1, we will determine the neutralizing potency of various antisera in susceptible lung cancer cells versus non-cancer respiratory tissue, and antibody dependent cellular cytotoxicity activities of antibodies in lung cancer versus normal lung epithelial cells. Lastly, we will determine the preclinical activity of drugs under clinical trial consideration in lung cancer cells vs. non-cancer respiratory tissue. Successful completion of these aims depend on our multi-disciplinary team, the clinical cohorts, biospecimens and resources provided by the Clinical and Data Sciences Cores and coordinated with overall U54 activities by the Administrative Core. In sum, these studies will provide new information on the determinants of the susceptibility of lung cancer patients to SARS-CoV-2 infection and uncover potential new therapeutic strategies.

项目2：摘要 项目2的依据是，肺癌患者对SARS-CoV-2感染的易感性较高， 严重疾病和死亡的风险增加。这种脆弱性的增加可能是由于以下因素的结合 因素，包括癌症本身或其治疗的免疫抑制作用，年龄，预先存在的 合并症或吸烟。此外，SARS-CoV-2受体ACE2的潜在升高水平， 在癌症患者和吸烟者的肺中观察到的肿瘤和肿瘤附近的正常组织中的蛋白质 个体可能有助于这些患者对SARS-CoV-2的易感性。肿瘤细胞也是已知的 由于先天性抗病毒免疫缺陷，更允许病毒复制。有可能增加 肺癌细胞中SARS-CoV-2扩增可能是导致COVID-19增强的主要因素 肺癌患者的症状这些患者肺细胞对病毒感染和复制的易感性增加， 患者也可能影响中和抗体阻断病毒复制的能力， 患者对SARS-CoV-2感染更敏感，免疫能力较低。一个更好的 需要了解影响SARS-CoV-2在肺癌和正常肺细胞中复制的因素 用于制定策略以降低肺癌患者患严重COVID-19疾病的风险，并用于评估 未来SARS-CoV-2疫苗在这些患者中的保护效果。为了弥补这些知识差距， 在目标1中，我们将确定与SARS感染易感性个体间差异相关的因素- CoV-2使用现有的独特的一组人肺癌衍生的癌细胞和正常上皮细胞，并将这些细胞与 关键临床、人口统计学和分子特征的因素。我们将使用病毒学和 基因组学方法、转录组学和scRNAseq测定。对SARS易感性的特异性- 将通过与其他呼吸道病毒（如流感病毒）进行比较来评价CoV-2感染。在aim中 2、我们将描述抗体和抗病毒药物在易感肺癌和正常人中的功能活性， 肺上皮细胞与项目1一起，我们将确定各种抗血清的中和效力， 易感肺癌细胞与非癌呼吸道组织，以及抗体依赖性细胞毒性 肺癌与正常肺上皮细胞中的抗体活性。最后，我们将确定临床前 临床试验中考虑的药物在肺癌细胞与非癌呼吸道组织中的活性。成功 这些目标的实现取决于我们的多学科团队、临床队列、生物标本和资源 由临床和数据科学核心提供，并与 行政核心。总之，这些研究将提供新的信息的决定因素的易感性 肺癌患者的SARS-CoV-2感染，并发现潜在的新的治疗策略。