Role of microbial-modulated bile acid receptor signaling in breast cancer

微生物调节胆汁酸受体信号传导在乳腺癌中的作用

基本信息

批准号：
10053592
负责人：
Liza Makowski-Hayes
金额：
$ 41.73万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10053592
关键词：
7alpha hydroxylase Ablation Address Adjuvant Affect Aggressive behavior Agonist Antibiotics Bile Acids Blood Circulation Body Weight decreased Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Cell Communication Cells Clinical Data Dietary Intervention Enterohepatic Circulation Estrogen Receptors Generations Genetic Goals Growth Human Hydroxylation Immune Immune checkpoint inhibitor Immunologic Surveillance Immunosuppression Immunotherapeutic agent Immunotherapy Implant In Vitro Incidence Intestinal Neoplasms Intestines Knowledge Link Liver Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Mediator of activation protein Metabolic Microbe Modeling Modification Mus Neoplasm Metastasis Obesity Outcome Pathologic Pathway interactions Patient-Focused Outcomes Patients Pharmacology Physiological Play Primary carcinoma of the liver cells Race Receptor Signaling Relapse Reporting Role Sampling Secondary to Shapes Signal Transduction Stromal Cells Testing Therapeutic Time Tissues Treatment Efficacy Tumor Immunity Tumor Markers Tumor Subtype Tumor stage Weight Work bacterial metabolism bariatric surgery breast cancer progression cancer cell cancer immunotherapy cancer subtypes carcinogenicity chemotherapy commensal microbes experimental study fecal transplantation gain of function gut microbiome gut microbiota host microbiota improved innovation malignant breast neoplasm microbial microbial community microbiome microbiome alteration microbiome research microbiota migration mimetics nonhuman primate novel novel therapeutics personalized medicine precision medicine receptor receptor expression response small molecule targeted treatment therapeutic evaluation triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

SUMMARY Anti-tumor immunity varies due to interactions between innate and adaptive immune cells, microbial community diversity, host and microbially derived metabolites, and other local factors that shape tumoricidal responses. While most of the recent microbiome research focuses on the gut microbiome and cancer outcomes, extra-intestinal microbial communities are detected in the tumor microenvironment (TME). We recently reported that specific microbes identified in patient breast tumors compared to pathologically normal breast samples associated with tumor stage, tumor subtype, and for the first time, race. Triple Negative Breast Cancer (TNBC), an aggressive subtype that has generally eluded personalized medicine approaches, contained unique microbes that may mediate immunosuppression and impact standard chemotherapy or immune checkpoint inhibitor (ICI) efficacies. Yet to date, mechanisms underpinning these observations are unresolved as to how the gut and/or extra-intestinal microbiome influence BC onset, progression, and response to therapies, which is a major knowledge gap in this field. One cogent mechanism that may link microbes to anti-tumor immunity are microbially modified metabolites, namely bile acids. Certain microbes rich in 7-alpha-hydroxylase convert primary to secondary bile acids which regulate bile acid composition. Bile acids have been shown to limit progression and metastasis in other cancers through reversing immunosuppression, but minimal work has explored the role of bile acids in BC. Bile acids signal through several bile acid receptors including farnesoid X receptor (FXR). We posit that specific gut or local resident microbes that impact bile acid pools and composition will interact with cells expressing FXR to regulate the TME immune milieu. We report for the first time that patients with high FXR expression have greater relapse-free survival uniquely in TNBC subtype, but not in less aggressive luminal BC subtype, suggesting potential for targeted approaches. The overall objective of this proposal is to test mechanisms linking MicrobesBile AcidsTNBC which poses an opportunity to generate novel therapeutics and precision medicine informed by microbial compositions. Our innovative approach interrogates targetable microbial pathways that we demonstrate change the microbiome, bile acids, and tumor progression. Our central hypothesis is microbial composition and microbially-modified metabolic products, such as bile acids, increase immunotherapeutic efficacy through reprogramming the TME leading to enhanced anti-tumor immunity. We will test our hypothesis by performing the following aims: 1) Determine if commensal microbes play a physiological role in TNBC anti-tumor immunity; 2) Determine if the microbiome alters immunosurveillance of early tumor onset and progression; 3) Determine if pharmacologic bile acid receptor agonism improves TNBC immunotherapy. Findings generated will have high impact because the lack of targeted therapies for TNBC presents a great unmet clinical need and could be transformative to improve patient outcomes.

概括由于先天和适应性免疫细胞之间的相互作用，微生物的抗肿瘤免疫学变化社区多样性，宿主和微生物衍生的代谢产物以及其他局部因素，这些因素塑造了结核回答。虽然大多数最近的微生物组研究都集中在肠道微生物组和癌症上结果，在肿瘤微环境（TME）中检测到肠外微生物群落。我们最近报道，与病理正常相比，患者乳腺肿瘤中发现的特定微生物与肿瘤阶段，肿瘤亚型以及首次种族相关的乳房样品。三重负乳房癌症（TNBC），一种积极的亚型，通常避免了个性化医学方法，包含可能介导免疫抑制并影响标准化学疗法或免疫检查点抑制剂（ICI）效率。迄今为止，这些观察的基础的机制是关于肠道和/或肠外微生物组如何影响BC发作，进展和对疗法的反应，这是该领域的主要知识差距。一种可能链接的有力机制抗肿瘤免疫学的微生物是微生物修饰的代谢产物，即胆汁酸。某些微生物丰富在7-α-羟化酶中，一级胆汁酸会转化为调节胆汁酸组成的次生胆酸。胆汁酸已显示通过逆转免疫抑制，可以限制其他癌症的进展和转移，但是最少的工作探索了胆汁酸在卑诗省的作用。胆汁酸通过几个胆汁酸受体信号包括Farnesoid X受体（FXR）。我们肯定会影响胆汁酸的特定肠道或当地居民微生物池和组成将与表达FXR的细胞相互作用以调节TME免疫环境。我们报告 FXR表达高的患者第一次在TNBC中独特地具有更大的无退休生存率亚型，但不在侵略性的腔内BC亚型中，这表明有针对性的方法的潜力。这该提案的总体目的是测试将微生物连接的机制孔酸TNBC，该机制位于通过微生物组合物告知的新型疗法和精确医学的机会。我们的创新方法询问了可靶向的微生物途径，我们证明了改变微生物组，胆汁酸和肿瘤进展。我们的中心假设是微生物组成和微生物修饰代谢产物，例如胆汁酸，通过重新编程TME提高免疫治疗效率导致抗肿瘤免疫增强。我们将通过执行以下目的来检验我们的假设：1）确定共生微生物是否在TNBC抗肿瘤免疫史上起身体作用； 2）确定是否微生物组改变早期肿瘤发作和进展的免疫监视； 3）确定是否药理胆汁酸受体激动剂改善了TNBC免疫疗法。产生的发现将产生很大的影响，因为缺乏针对性TNBC的有针对性疗法提出了巨大的未满足的临床需求，并且可以转变为改善患者的预后。