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.

根据初步血清学检测，纽约市地区已成为美国COVID-19大流行的热点地区，估计患病率为20%。严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）在癌症患者中的患病率增加，预后较差。SARS-CoV-2患者更容易出现促炎细胞因子如IFN-、IP-10、MCP-1、IL-1、IL-4和IL-6的升高，其中许多与肺癌的发病机制和免疫检查点抑制剂（ICI）相关不良事件的发生有关。然而，既往SARS-CoV-2感染对癌症发病机制和免疫治疗反应的影响尚不清楚。在我们的父母R37资助下，我们研究了下气道失调对宿主免疫调节、肺癌发病机制和免疫治疗反应的作用。使用和扩大在母体R37下集合的队列，我们将评估SARS-CoV-2感染是否影响下气道免疫音调，促进促肿瘤免疫和ici相关肺炎。为了验证这一点，我们将测试在新诊断的非小细胞肺癌患者中，先前的SARS-CoV-2感染是否与肿瘤炎症相关（New Aim 4），以及SARS-CoV-2是否使患者易患ci相关性肺炎（New Aim 5）。为了实现这些目标，我们将利用我们在表征下气道微生物组（包括病毒部分）和宿主免疫谱方面的专业知识。我们还将利用纽约地区COVID-19血清阳性率高的优势，并从我们已建立的支气管镜检查和胸外科队列中收集样本。此外，我们将使用一种新的RNA序列方法，允许同时表征下气道中的RNA病毒组、细菌微生物组和宿主转录组。因此，在亲本R37建立的基础设施下，对SARS-CoV-2感染对癌症病理生理的影响进行必要的探索性研究是一个前所未有的机会。