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

• 批准号: 10555291
• 负责人: Humam Kadara
• 金额: $ 52.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/10555291
• 关键词: 16S ribosomal RNA sequencing; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; 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; Immunology; Immunotherapeutic agent; Immunotherapy; Inferior; Inflammation; Inflammatory; Interleukin-6; Intervention; Ketones; Knock-out; LCN2 gene; Link; Lung; Lung Adenocarcinoma; Lung Neoplasms; Lung immune response; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metagenomics; Modality; Molecular; Mus; Mutation; Neoadjuvant Therapy; Nicotine; Nitrosamines; Oncogenes; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; 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; Tumor Promotion; 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; pharmacologic; prevent; probiotic supplementation; programmed cell death protein 1; programs; response; statistics; tobacco exposure; treatment response; tumor; tumor progression; tumorigenesis

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）是终生吸烟者中最常见的癌症， 超过9000万在美国。LUAD的吸烟者经常（超过25%）携带体细胞 激活Kras癌基因突变。Kras突变型LUAD（KM-LUAD）的临床结局非常差 和对治疗的低反应尽管迫切需要新的策略来早期治疗这种致命的 疾病，我们仍然不了解促进KM-LUAD发作的靶向变化。利用人类- 包括烟草暴露和高体细胞突变的相关基因工程小鼠模型 负担，包括驱动Kras变体，构成LUAD发病机制的完美风暴的特征， 在人类中，我们发现肠道微生物组组成发生了显著的进行性变化， 肠道和循环细菌代谢物水平降低，与KM-LUAD的演变密切相关。 在暴露于可燃香烟烟雾（CCS）的小鼠中观察到类似的微生物表型。我们 在小鼠的肺中进一步发现促肿瘤炎症因子的上调，包括IL-6的活化， /STAT 3通路，我们以前已经表明，促进KM-LUAD的发展，通过免疫 重新编程此外，我们注意到脂质运载蛋白2（LCN 2），一种宿主防御抗菌蛋白， 在正常气道细胞中， Kras突变体瘤前病变和LUAD的发病。这些小鼠中Lcn 2的遗传缺失显著增加 KM-LUAD的发展伴随着肠道微生物组的全球变化和促肿瘤肺的增加 炎症尽管有这些见解，但宿主微生物组和免疫系统中关键免疫反应之间的相互作用， KM-LUAD的发病机制尚不清楚。我们假设宿主微生物组（来源于 从肠道和可能的肺）促进烟草相关的KM-LUAD的发展， IL-6/STAT 3通路的激活以及全身和肺免疫结构的变化。我们将 用以下三个目标来解决我们的假设。在目标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，我们将辨别不断变化的微生物组变化， 与烟草致癌物和CCS相关的KM-LUAD发展以及探针功能相关 下游全身和局部（肺中）免疫调节作用，包括对促肿瘤IL-12的免疫调节作用。 6/STAT 3通路。在目标2中，我们将确定宿主抗菌和免疫调节因子的作用 在KM-LUAD发病机制中由LCN 2诱导介导。在目标3中，我们将研究化学预防和 微生物组干预的早期治疗效果，单独或与免疫疗法联合，对KM- LUAD。在我们的研究结束时，我们将阐明在进化过程中未知的宿主过程。 KM-LUAD，为识别新靶点铺平了道路，以指导化学预防和早期检测。 吸烟者的致命疾病，并为研究LUAD发病机制提供了新的模型。