Interplay between host microbiome and immunomodulatory responses in the pathogenesis of Kras mutant lung cancer

Kras 突变肺癌发病机制中宿主微生物组与免疫调节反应之间的相互作用

基本信息

批准号：
10356940
负责人：
Humam Kadara
金额：
$ 54.07万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-19 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10356940
关键词：
16S ribosomal RNA sequencing 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone Address Animals Antibiotics Antibodies Bioinformatics Cancer Patient Carcinogen exposure Cells Chemoprevention Chemopreventive Agent Clinical Cues Data Development Disease Early Diagnosis Early treatment Event Evolution Exhibits Experimental Models Exposure to Fostering G-Protein-Coupled Receptors Genetic Genetically Engineered Mouse Global Change Health Host Defense Human Immune Immune response Immunotherapeutic agent Immunotherapy Inferior Inflammation Inflammatory Interleukin-6 Intervention Ketones Knock-out LCN2 gene Light Link Lung Lung Adenocarcinoma Lung immune response Malignant Neoplasms Malignant neoplasm of lung Mediating Metagenomics Modality Molecular Target Mus Mutation Neoadjuvant Therapy Nicotine Nitrosamines Oncogenes Outcome Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phenotype Prevention strategy Process Prognosis Proteins Pulmonary Inflammation Reporting Role STAT3 gene Sampling Signal Transduction Smoker Smoking Somatic Mutation Structure of parenchyma of lung Study models T-Lymphocyte Taxonomy Testing Therapeutic Effect Time Tobacco Tobacco-Associated Carcinogen Tumor Immunity United States Up-Regulation Variant Volatile Fatty Acids Wild Type Mouse antimicrobial cancer diagnosis cancer therapy cigarette smoke combustible cigarette exposure to cigarette smoke gut microbiome host microbiome immune checkpoint immunoregulation insight lung microbiome microbial microbiome microbiome composition mouse model mutant novel nursing mothers prevent probiotic supplementation programmed cell death protein 1 programs response statistics tobacco exposure treatment response tumor tumor immunology tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Lung adenocarcinoma (LUAD) is the most common cancer diagnosed in lifetime smokers of whom there are more than 90 million in the United States. Smokers with LUAD frequently (more than 25%) harbor somatic activating mutations in the Kras oncogene. Kras-mutant LUAD (KM-LUAD) displays very poor clinical outcome and inferior response to therapy. Despite the urgent need of new strategies for early treatment of this fatal disease, we still do not understand targetable changes that promote onset of KM-LUAD. Using a human- relevant genetically engineered mouse model comprised of tobacco exposure and high somatic mutation burdens including driver Kras variants, features that constitute a perfect storm for LUAD pathogenesis in humans, we identified significant progressive changes in gut microbiome composition that were coexistent with reduced levels of gut and circulating bacterial metabolites and closely associated with evolution of KM-LUAD. Similar microbial phenotypes were observed in mice exposed to combustible cigarette smoke (CCS). We further found in lungs of the mice up-regulation of pro-tumor inflammatory cues including activation of the IL-6 /STAT3 pathway which we have previously shown to promote KM-LUAD development by immune reprogramming. Also, we noted that lipocalin 2 (LCN2), a host defense antimicrobial protein that is released from cells during microbiome imbalance, was markedly progressively up-regulated in normal airway cells prior to onset of Kras-mutant preneoplasias and LUADs. Genetic deletion of Lcn2 in these mice markedly increased KM-LUAD development concomitant with global changes in the gut microbiome and heightened pro-tumor lung inflammation. Despite these insights, the interplay between the host microbiome and key immune responses in the pathogenesis of KM-LUAD are poorly understood. We hypothesize that the host microbiome (derived from the gut and possibly the lung) promotes tobacco-associated KM-LUAD development through activation of the IL-6/STAT3 pathway and changes in systemic and lung immune contexture. We will address our hypothesis using the following three aims. In Aim 1, using sequencing, metagenomics, as well as bacterial metabolite and immune profiling approaches, we will discern evolving microbiome changes that are functionally linked to tobacco carcinogen- and CCS-associated KM-LUAD development as well as probe downstream systemic and local (in lung) immunomodulatory effects including those on the pro-tumor IL- 6/STAT3 pathway. In Aim 2, we will determine the role of host antimicrobial and immunomodulatory cues mediated by LCN2 induction in KM-LUAD pathogenesis. In Aim 3, we will investigate chemopreventive and early therapeutic effects of microbiome intervention, alone or in combination with immunotherapy, against KM- LUAD. At the conclusion of our studies, we will have shed light on uncharted host processes in the evolution of KM-LUAD, paved the way for identification of new targets to guide chemoprevention and early detection of this fatal disease in smokers and contributed novel models for studying LUAD pathogenesis.

项目摘要肺腺癌（LUAD）是终身吸烟者中最常见的癌症在美国，超过9000万。 luad的吸烟者经常（超过25％）激活KRAS癌基因中的突变。 Kras突变luad（km-luad）表现出非常差的临床结果和对治疗的劣等反应。尽管迫切需要新策略来早期治疗这种致命疾病，我们仍然不了解促进KM-LUAD发作的目标变化。使用人类相关的基因工程小鼠模型由烟草暴露和高体细胞突变组成包括驾驶员Kras变体在内的负担，构成了LUAD发病机理的完美风暴的功能人类，我们确定了肠道微生物组组成的重大渐进变化肠道和循环细菌代谢物的水平降低，与KM-Luad的进化密切相关。在暴露于可燃香烟烟雾（CCS）的小鼠中观察到了类似的微生物表型。我们在小鼠的肺中进一步发现了促肿瘤炎症提示，包括激活IL-6 /STAT3途径，我们以前证明，通过免疫来促进KM-Luad的发展重新编程。另外，我们注意到Lipocalin 2（LCN2），一种释放的宿主防御抗菌蛋白从微生物组失衡期间的细胞中，在正常气道细胞中明显逐渐上调为了发作Kras突变的肿瘤和luads。 LCN2在这些小鼠中的遗传缺失显着增加 KM-LUAD的发展与肠道微生物组的全球变化并增强了肿瘤肺炎。尽管有这些见解，但宿主微生物组和关键免疫反应之间的相互作用 KM-LUAD的发病机理知之甚少。我们假设主机微生物组（得出从肠道和可能的肺）通过 IL-6/STAT3途径的激活以及系统性和肺免疫情境的变化。我们将使用以下三个目标解决我们的假设。在AIM 1中，使用测序，宏基因组学以及细菌代谢物和免疫分析方法，我们将辨别出不断发展的微生物组变化在功能上与烟草致癌和CCS相关的KM-LUAD发育以及探针有关下游的系统性和局部（肺中）免疫调节作用，包括对肿瘤的IL- 6/STAT3途径。在AIM 2中，我们将确定宿主抗菌和免疫调节提示的作用由LCN2诱导介导的KM-Luad发病机理。在AIM 3中，我们将研究化学预防和微生物组干预的早期治疗作用，单独或与免疫疗法结合使用，对KM- 卢德。在我们的研究结束时，我们将阐明未知的宿主过程 KM-Luad，为识别新目标铺平了指导化学预防和早期检测的道路吸烟者的致命疾病，并为研究LUAD发病机理贡献了新的模型。