Metabolite driven mechanisms by which gut microbes impact checkpoint inhibitor success in non-small cell lung cancer patients

肠道微生物影响检查点抑制剂在非小细胞肺癌患者中成功的代谢驱动机制

• 批准号: 10281842
• 负责人: Fyza Y Shaikh
• 金额: $ 21.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10281842
• 关键词: Address; Adenosine Monophosphate; Affect; Antitumor Response; Bacteria; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Patient; Cessation of life; Characteristics; Classification; Clinical; Clinical Treatment; Colonic Neoplasms; Communities; Cytotoxic T-Lymphocytes; DNA; Data; Deaminase; Disease; Disease Progression; Distant; Environment; Enzymes; Exhibits; Feces; Foundations; Genes; Germ-Free; Glucose; Goals; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunotherapy; Inosine; Interferons; Intervention Studies; Literature; Longitudinal Studies; Malignant Neoplasms; Metagenomics; Microbe; Modeling; Mus; Mutation; Neoplasm Transplantation; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Physicians; Plasma; Production; Propionates; Publishing; Reporting; Resistance; Ribosomal RNA; Sampling; Scientist; Site; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; Testing; Therapeutic; Training; Translations; Tumor-infiltrating immune cells; Validation; Volatile Fatty Acids; anti-PD-L1; anti-PD-L1 therapy; bacterial community; base; cancer therapy; career development; checkpoint therapy; clinical practice; cohort; data integration; fatty acid metabolism; fecal microbiota; genome sequencing; gut bacteria; gut microbes; gut microbiome; high dimensionality; human microbiota; improved; indexing; innovation; longitudinal analysis; melanoma; metabolomics; microbial; microbial community; microbiome; microbiota metabolites; mouse model; novel; predictive marker; responders and non-responders; response; single-cell RNA sequencing; stool sample; study population; success; tumor; tumor microenvironment; tumorigenic; whole genome

ABSTRACT Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but clinical responses remain limited due to primary and/or acquired ICI resistance. Preliminary studies suggest the gut microbiome is an independent, novel modulator of systemic and intra-tumoral responses to ICIs. Published studies, primarily in melanoma and non-small cell lung cancer (NSCLC), reported a diverse gut microbiome and a few bacterial species associated with tumor responses to ICIs. However, existing studies are limited by an oversimplified classification of responder status and lack of longitudinal analysis. Moreover, specific bacteria or bacterial communities putatively helpful or harmful to ICI responses have largely been inconsistent across study populations and tumor types with only limited correlations with immune or mutational biomarkers. To address these inconsistencies, we reanalyzed raw 16S rRNA amplicon and whole genome sequencing (WGS) fecal data from five published studies (n=303, pre-treatment stools only) using a high dimensional computational approach and found that our predictive index underperformed in NSCLC, the leading cause of cancer death, compared to melanoma. Thus, to further refine this index and identify mechanisms of action for the microbiome in NSCLC ICI therapy, herein, we propose detailed metabolite (plasma, fecal) and metagenomic (fecal, WGS) longitudinal studies of our NSCLC cohort (n=108). We will focus our studies on patients with a durable response to ICIs, comparing them to those with primary resistance (disease progression within 6 months) or acquired resistance (disease progression after an initial response >6 months). Microbiota metabolite production, with the capacity to impact local and systemic immune responses, is proposed as a ‘common pathway’ mechanism promoting anti-tumor responses. For example, both recent literature and our preliminary data in transplantable tumor murine models suggest inosine and short chain fatty acids (SCFA) are microbial modifiers of the tumor microenvironment. Further, a preliminary study found SCFAs enriched in fecal sample from NSCLC patients with durable response to ICIs (n=11). We hypothesize that specific bacterial species and/or communities promote production of SCFAs and/or inosine in the gut and plasma of NSCLC patients who exhibit durable responses to ICI therapy whereas these are absent in patients who exhibit primary and/or ultimately develop acquired resistance. To test our hypothesis, we propose to identify fecal and/or plasma metabolites (SA1) and/or microbial taxa (SA2) that correlate with durable response or ICI resistance in NSCLC patients. We will further test our hypothesis by defining the intra-tumoral immune cell response to our patient cohorts in syngeneic murine tumor models using single cell RNAseq and paired T cell receptor sequencing to define T cell repertoires (SA3). Our multidimensional approach, with both cross-sectional and longitudinal translational analysis, will help define key metabolites and microbes that impact ICI resistance in NSCLC. These studies will be foundational to my transition to independence as a physician-scientist and will set the stage for consideration of interventional studies in NSCLC patients.

摘要 免疫检查点抑制剂（ICI）已经彻底改变了癌症治疗，但临床反应仍然有限 由于原发性和/或获得性ICI抗性。初步研究表明，肠道微生物组是一个独立的， 对ICI的全身和肿瘤内反应的新型调节剂。已发表的研究，主要是黑色素瘤和 非小细胞肺癌（NSCLC），报告了多种肠道微生物组和一些相关的细菌物种 肿瘤对ICIs的反应。然而，现有的研究受到过度简化的分类的限制。 响应者状态和缺乏纵向分析。此外，特定的细菌或细菌群落可以 对ICI反应的有益或有害在很大程度上与研究人群和肿瘤类型不一致， 仅与免疫或突变生物标志物有限相关。为了解决这些矛盾，我们重新分析了 来自5个已发表研究的原始16 SrRNA扩增子和全基因组测序（WGS）粪便数据（n=303， 仅治疗前粪便），并发现我们的预测指数 与黑色素瘤相比，在NSCLC中表现不佳，NSCLC是癌症死亡的主要原因。为了进一步完善 这一指数和确定作用机制的微生物组在NSCLC ICI治疗，在此，我们建议 我们NSCLC队列的详细代谢物（血浆、粪便）和宏基因组（粪便、WGS）纵向研究 （n=108）。我们将把研究重点放在对ICIs有持久反应的患者上，将他们与那些对ICIs有持久反应的患者进行比较。 原发性耐药（6个月内疾病进展）或获得性耐药（6个月后疾病进展） 初始反应>6个月）。微生物群代谢产物的产生，具有影响局部和全身的能力 免疫应答，被认为是促进抗肿瘤应答的“共同途径”机制。为 例如，最近的文献和我们在可移植肿瘤小鼠模型中的初步数据都表明肌苷 和短链脂肪酸（SCFA）是肿瘤微环境的微生物调节剂。此外，初步 研究发现SCFA富集在来自对ICI具有持久应答的NSCLC患者的粪便样本中（n=11）。我们 假设特定细菌物种和/或群落促进SCFA和/或肌苷的产生 对ICI治疗表现出持久应答的NSCLC患者的肠道和血浆，而这些患者不存在 在表现出原发性和/或最终发展为获得性耐药的患者中。为了验证我们的假设，我们建议 鉴定与持久反应相关的粪便和/或血浆代谢物（SA 1）和/或微生物分类群（SA 2） 或ICI耐药。我们将通过定义肿瘤内免疫细胞来进一步验证我们的假设。 使用单细胞RNAseq和配对T细胞在同基因小鼠肿瘤模型中对我们的患者队列的反应 受体测序以确定T细胞库（SA 3）。我们的多维方法，既有横截面 和纵向翻译分析，将有助于确定影响ICI抗性的关键代谢物和微生物 在NSCLC中。这些研究将是我作为一名物理学家-科学家向独立过渡的基础， 为考虑在NSCLC患者中进行干预性研究奠定基础。