Local microbiota signatures of pro-tumor immunity and checkpoint inhibition susceptibility in lung cancer

肺癌中促肿瘤免疫和检查点抑制敏感性的局部微生物群特征

• 批准号: 10202873
• 负责人: Leopoldo Nicolas Segal
• 金额: $ 16.95万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202873
• 关键词: 2019-nCoV; Acute respiratory infection; Adverse event; Affect; Antibodies; Antigen Receptors; Area; Biological Process; Blood specimen; Bronchoscopy; CCL2 gene; COVID-19; COVID-19 pandemic; CXCL10 gene; Cancer Patient; Case Study; Cells; Cessation of life; China; Complex; Data; Development; Early Detection Research Network; Encephalitis; Environment; Epstein-Barr Virus Infections; Event; Excision; Functional disorder; Funding; Grant; Health; Hot Spot; Immune; Immune checkpoint inhibitor; Immune system; Immunity; Immunotherapy; Individual; Infection; Inflammation; Infrastructure; Intensive Care Units; Interferons; Interleukin-1; Interleukin-4; Interleukin-6; Investigation; Link; Lung; Lung nodule; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Microbe; Myocarditis; New York; New York City; Newly Diagnosed; Non-Small-Cell Lung Carcinoma; Oligonucleotides; Organ; Outcome; Parents; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Prevalence; Prospective cohort; Pulmonary Inflammation; RNA; RNA Sequences; Recording of previous events; Role; Sampling; Serologic tests; Serological; Surface; Testing; Thoracic Surgical Procedures; Time; United States; Viral; Virus; acute infection; anti-PD-1; anti-PD-L1; bacteriome; base; biobank; cancer diagnosis; checkpoint inhibition; cohort; cytokine; dysbiosis; high risk; innovation; longitudinal design; microbial; microbiota profiles; novel; novel coronavirus; outcome forecast; respiratory microbiome; response; sample collection; seropositive; transcriptome; transcriptome sequencing; treatment response; tumor microenvironment; ventilation; virome

The New York City area has become the hot spot of the COVID-19 pandemic in the United States with an estimated prevalence of >20%, based on preliminary serological tests. The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is increased among cancer patients, and their prognosis is worse. Patients with SARS-CoV-2 are more likely to have increased proinflammatory cytokines such as IFN-, IP-10, MCP-1, IL-1, IL-4 and IL-6, many of which have been associated with the pathogenesis of lung cancer and the development of immune checkpoint inhibitor (ICI) -related adverse events. However, the effects of prior SARS-CoV-2 infection on cancer pathogenesis and response to immunotherapy are not know. Under our parent R37 grant, we investigate the role of lower airway dysbiosis on the host immune tone, lung cancer pathogenesis, and the response to immunotherapy. Using and expanding the cohort ensembled under the parent R37 we will evaluate whether SARS-CoV-2 infection affects the lower airway immune tone promoting pro-tumor immunity and ICI-related pneumonitis. To test this, we will test whether prior SARS-CoV-2 infection is associated with protumor inflammation among patients with newly diagnosed NSCLC (New Aim 4) and whether SARS-CoV-2 predisposes patients to ICI-related pneumonitis (New Aim 5). To accomplished these aims we will use our expertise in the characterization of the lower airway microbiome (including the viral fraction) and the host immune profile. We will also take advantage of the high rate of COVID-19 seropositivity in the New York area and the collection of samples from our established bronchoscopy and thoracic surgery cohorts. In addition, we will use a novel RNA sequence approach that allows for the concomitant characterization of the RNA virome, the bacterial microbiome and he host transcriptome in the lower airways. Therefore, this is an unprecedented opportunity to conduct the necessary exploratory investigations on the effects of SARS-CoV-2 infection on the pathophysiology of cancer under the infrastructure established by the parent R37.

根据初步的血清学测试，纽约市地区已成为美国199日大流行的热点，估计患病率> 20％。癌症患者的严重急性呼吸综合征2（SARS-COV-2）的患病率增加，预后较差。患有SARS-COV-2的患者更可能增加促炎细胞因子，例如IFN-，IP-10，MCP-1，IL-1，IL-4和IL-6，其中许多与肺癌的发病机理和Immunocheckpoint抑制剂（ICI）引起的不良反相事件有关。然而，尚不清楚先前的SARS-COV-2感染对癌症发病机理和对免疫疗法的反应的影响。在我们的父级R37授予下，我们研究了较低的气道营养不良对宿主免疫张力，肺癌发病机理以及对免疫疗法的反应的作用。使用并扩展了在父r37下结合的队列，我们​​将评估SARS-COV-2感染是否影响较低的气道免疫酮促进促肿瘤免疫力和与ICI相关的肺炎。为了测试这一点，我们将测试先前的SARS-COV-2感染是否与已诊断为NSCLC的患者的原始感染有关（新目标4）以及SARS-COV-2患者是否易于ICI相关的肺炎（新AIM 5）。为了实现这些目标，我们将使用我们的专业知识来表征下气道微生物组（包括病毒分数）和宿主免疫轮廓。我们还将利用纽约地区的COVID-19 Serapitivitive的高率，以及我们已建立的支气管镜检查和胸外手术队列中的样品收集。此外，我们将使用一种新型的RNA序列方法，可以允许对RNA病毒组，细菌微生物组和他在下部气道中的转录组的同时表征。因此，这是一个前所未有的机会，可以对SARS-COV-2感染对父母R37建立的基础设施下的SARS-COV-2感染对癌症病理生理的影响进行必要的探索性投资。