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

抽象的。尽管美国的吸烟率在下降，但肺癌仍然是主要的原因 癌症死亡人数。用PD-1阻断治疗肺癌已成为大多数非小细胞肺癌的一线治疗 细胞肺癌(NSCLC)。然而，考虑到免疫疗法在这种疾病中的不同效果，有 需要更好地了解影响个体对这种疗法反应的因素。肺微生物区系发挥作用 在影响受试者对炎症性呼吸道疾病易感性的宿主免疫反应中起着重要作用。 我们已经证明，下呼吸道微生物区系与下呼吸道的Th17表型相关。在……里面 肺癌，我们在下呼吸道中发现了一种称为肺炎型SPT的非生物信号，它与 与肺癌发生相关的转录转录特征。我们的初步数据显示，患有 以肺炎型为特征的下呼吸道微生物群可能会增加死亡率和增强免疫力 检查点禁止的音调。虽然肠道微生物区系特征与PD-1阻断反应部分相关， 下呼吸道微生物区系对免疫张力和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物失调(肺炎型)改变了宿主的炎症。 肿瘤微环境中的表型影响对PD-1阻断的反应。为了研究这一点，我们将 使用科学严谨的方法进行这项病理生理调查 晚期肺癌患者PD-1阻断治疗前后的呼吸道、粪便和血样采集 非小细胞肺癌。我们将通过以下方法评估与PD-1阻断相关的受试者的呼吸道/粪便微生物特征 无进展生存的纵向评估(目标1)。此外，我们还将进行纵向表演 对呼吸道、粪便和血液进行采样，以扩大我们对呼吸道、粪便和血液动态变化的机械理解 PD-1阻断治疗期间的微生物群和宿主免疫反应(目标2)。验证和扩展 微生物组和宿主炎症情况的评估将通过使用互补的 方法(微生物区系：16S rRNA基因和偏转录组测序；炎症：呼吸道刷子 转录组、多染色流式细胞术和T细胞的单细胞RNA测序)。在目标3中，我们将使用 临床前的小鼠肺癌模型，将使我们能够评估下呼吸道生物失调的影响 免疫调节和PD-1阻断易感性。识别影响反应的微生物特征 这种一线治疗将是个性化治疗方法的关键，并将确定新的可修改的靶点。 版面总结。肺癌是美国癌症死亡的主要原因，其治疗一直是 通过使用免疫疗法而发生了革命性的变化。然而，对这种疗法的反应是可变的和最新的数据 表明寄生在我们体内的微生物(称为微生物组)可以影响受试者个体的反应。在……里面 在这个项目中，我们将发现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.