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

基本信息

批准号：
10320008
负责人：
Leopoldo Nicolas Segal
金额：
$ 65.28万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320008
关键词：
16S ribosomal RNA sequencing Affect Airway Disease Antitumor Response Biological Markers Blood Blood specimen Cancer Etiology Cancer Model Cells Cessation of life Chara Characteristics Clinical Clinical Trials Color Data Disease Distant Early identification Effectiveness Etiology Evaluation Feces Flow Cytometry Grant IL17 gene Immune Immune response Immunity Immunotherapy Inflammation Inflammatory Interleukin-17 Intervention Investigation Link Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Methods Microbe Modeling Modification Mus Newly Diagnosed Non-Small-Cell Lung Carcinoma Oral Outcome Pathway interactions Patients Phenotype Play Pre-Clinical Model Predisposition Prevalence Prevotella Progression-Free Survivals RNA Ribosomal RNA Role Sampling T cell response T-Lymphocyte Taxonomy Testing Tumor Burden Tumor Immunity Validation Veillonella airway inflammation base checkpoint inhibition design dysbiosis gut microbiota gut-lung axis immune checkpoint individual response innovation longitudinal design lung carcinogenesis lung microbiota metatranscriptome metatranscriptomics microbial microbial signature microbiome microbiome research microbiota microbiota profiles mortality mouse model mucosal microbiota multiple omics neoantigens novel personalized therapeutic pre-clinical predicting response primary outcome programmed cell death ligand 1 programmed cell death protein 1 prospective rRNA Genes respiratory microbiota response risk stratification single-cell RNA sequencing smoking prevalence stool sample therapy outcome trait transcriptome transcriptome sequencing transcriptomics treatment responders treatment response tumor tumor microenvironment

项目摘要

Abstract. Despite the declining prevalence of smoking in the US, lung cancer continues to be the leading cause of cancer deaths. Treatment of lung cancer with PD-1 blockade has become first line therapy of most non-small cell lung cancer (NSCLC). However, given the variable effectiveness of immunotherapy in this disease there is a need to better understand factors that affect individual’s response to this therapy. The lung microbiota plays an important role in host immune responses affecting subject’s susceptibility to inflammatory airway diseases. We have demonstrated that lower airway microbiota is associated with Th17 phenotype in the lower airways. In lung cancer, we identified a dysbiotic signature in the lower airways called pneumotypeSPT that is associated with transcriptomic signatures associated with lung carcinogenesis. Our preliminary data shows that subjects with lower airway microbiota characterized as pneumotypeSPT may have increased mortality and increased immune checkpoint inhibited tone. While gut microbiota signatures are partially associated with PD-1 blockade response, the effects of the lower airway microbiota on the immune tone and PD-1 blockade susceptibility are not known. Thus, we hypothesize that lower airway dysbiosis (pneumotypeSPT) alters the host inflammatory phenotype in the tumor microenvironment affecting the response to PD-1 blockade. To study this, we will utilize a scientifically rigorous approach to conduct this pathophysiological investigation using prospective airway, stool, and blood samples collected before and after PD-1 blockade treatment of subjects with advanced NSCLC. We will evaluate airway/stool microbial signatures associated subjects’ response to PD-1 blockade by longitudinal assessment of the progression free survival (Aim 1). In addition, we will perform longitudinal sampling of airways, stool, and blood to expand our mechanistic understanding of the dynamic changes in the microbiome and host immune response during PD-1 blockade treatment (Aim 2). Validation and extension of the assessment of the microbiome and host inflammatory profile will be accomplished by using complementary approaches (microbiota: 16S rRNA gene and metatranscriptome sequencing; inflammation: airway brush transcriptome, polychromatic flow cytometry, and single cell RNA sequencing of T cells). In Aim 3 we will use a preclinical mouse model of lung cancer that will allow us to evaluate the effects of dysbiosis on the lower airway immune tone and PD-1 blockade susceptibility. Identification of microbial signatures that affect the response to this first line therapy will be key to a personalized therapeutic approach and will identify novel modifiable targets. Lay summary. The treatment of lung cancer, the leading cause of cancer deaths in the U.S., has been revolutionized by the use of immunotherapy. However, the response to this therapy is variable and recent data suggest that microbes that colonize our bodies (called microbiome) can affect subject individual’s response. In this project, we will uncover microbial signatures that affect the lung cancer treatment response to immunotherapy.

摘要。癌症死亡。但是，鉴于免疫疗法在该疾病中的有效有效性是需要更好地理解影响个人反应的因素。在影响受试者对炎症气道疾病易感性的宿主免疫反应中的重要作用。我们已经证明了较低的气道微生物群与下气道中的Th17表型有关肺癌，我们在称为肺炎的下部气道中鉴定出与与之相关的肺炎型的失调特征。转录组签名与肺癌发生有关。以肺炎型的特征的下气道微生物群可能增加了死亡率并增加了免疫免疫检查点抑制了，而肠道微生物群的特征则与PD-1封锁响应有关下气道微生物群对免疫音调和PD-1阻滞敏感性的影响尚不清楚。因此，我们假设较低的气道营养不良（元素型）改变了宿主炎症肿瘤微环境中的表型对PD-1的反应进行研究。利用科学严格的方法来进行病理生理研究 PD-1阻断治疗患者的气道，粪便和血液样本在患有晚期的受试者之前和之后采样 NSCLC。对无进展生存的纵向评估（AIM 1）。气道，凳子和血液的取样，以扩大我们对动态变化的机械理解 PD-1封锁处理过程中的微生物组和宿主免疫反应（AIM 2）。微生物组和宿主炎症轮廓的评估将通过使用补充来完成进近（微生物群：16S rRNA基因和元转录测序；炎症：气道刷转录组，多色流式细胞计和TCELL的单细胞RNA测序）。肺癌的临床前小鼠模型，这将使我们能够评估营养不良对下气道的影响免疫音调和PD-1阻断敏感性。这种第一行疗法将是个性化治疗方法的关键，并将确定可修改的新目标。总结肺癌的治疗，癌症死亡死亡死亡死亡死亡死亡死亡死亡死亡的主要原因通过使用免疫疗法革新。建议将我们的身体定居（称为微生物组）影响主体的反应这个项目，我们将发现微生物特征的肺癌治疗反应免疫疗法。