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

抽象的。尽管美国吸烟率下降，但肺癌仍然是主要原因。 癌症死亡人数。用PD-1阻断剂治疗肺癌已成为大多数非小细胞肺癌患者的一线治疗。 细胞肺癌（NSCLC）。然而，考虑到免疫疗法在这种疾病中的可变有效性， 需要更好地了解影响个体对这种疗法的反应的因素。肺部微生物群扮演着 在影响受试者对炎性气道疾病的易感性的宿主免疫应答中起重要作用。 我们已经证明下呼吸道微生物群与下呼吸道中的Th 17表型相关。在 在肺癌中，我们在下呼吸道中发现了一种称为pneumotypeSPT的微生态失调信号， 与肺癌发生相关的转录组学特征。我们的初步数据显示， 下呼吸道微生物群特征为肺型SPT可能会增加死亡率， 检查点抑制音。虽然肠道微生物群特征与PD-1阻断反应部分相关， 下呼吸道微生物群对免疫张力和PD-1阻断敏感性的影响尚不清楚。 因此，我们假设下呼吸道生态失调（肺型SPT）改变了宿主的炎症反应， 在肿瘤微环境中的表型影响对PD-1阻断的反应。为了研究这个问题，我们将 利用科学严谨的方法进行这项病理生理学研究， 在PD-1阻断治疗之前和之后收集的晚期哮喘受试者的气道、粪便和血液样本， NSCLC。我们将通过以下方法评估与受试者对PD-1阻断的反应相关的气道/粪便微生物特征： 无进展生存期的纵向评估（目标1）。此外，我们将执行纵向 呼吸道，粪便和血液的采样，以扩大我们对呼吸道动态变化的机械理解。 在PD-1阻断治疗期间，微生物组和宿主免疫应答（目的2）。验证和扩展 微生物组和宿主炎症谱的评估将通过使用互补的 方法（微生物群：16 S rRNA基因和元转录组测序;炎症：气道刷 转录组、多色流式细胞术和T细胞的单细胞RNA测序）。在目标3中，我们将使用 肺癌的临床前小鼠模型，这将使我们能够评估生态失调对下呼吸道的影响 免疫调节和PD-1阻断敏感性。鉴定影响对以下物质的反应的微生物特征 这种第一线疗法将是个性化治疗方法的关键，并将确定新的可改变的靶点。 简单总结。肺癌是美国癌症死亡的主要原因，已经 免疫疗法的使用彻底改变了这种疾病然而，对这种疗法的反应是可变的，最近的数据显示， 表明在我们身体中定居的微生物（称为微生物组）可以影响受试者个体的反应。在 在这个项目中，我们将揭示影响肺癌治疗反应的微生物特征， 免疫疗法

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.