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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.

概括抗肿瘤免疫因先天免疫细胞和适应性免疫细胞、微生物之间的相互作用而变化群落多样性、宿主和微生物衍生的代谢物以及其他影响肿瘤杀灭作用的局部因素回应。虽然最近大多数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，与病理正常的患者相比，在患者乳腺肿瘤中发现了特定的微生物乳房样本与肿瘤分期、肿瘤亚型相关，并且首次与种族相关。三阴性乳房癌症 (TNBC) 是一种侵袭性亚型，通常无法采用个性化医疗方法，含有独特的微生物，可能介导免疫抑制并影响标准化疗或免疫检查点抑制剂（ICI）的功效。然而迄今为止，支撑这些观察结果的机制是肠道和/或肠外微生物组如何影响 BC 的发病、进展和影响尚未解决对治疗的反应，这是该领域的一个主要知识差距。一种可能联系起来的令人信服的机制微生物发挥抗肿瘤免疫作用的是微生物修饰的代谢产物，即胆汁酸。富含某些微生物 7-α-羟化酶将初级胆汁酸转化为次级胆汁酸，从而调节胆汁酸的组成。胆汁酸已被证明可以通过逆转免疫抑制来限制其他癌症的进展和转移，但探索胆汁酸在 BC 中的作用的工作却很少。胆汁酸通过几种胆汁酸受体发出信号包括法尼醇X受体（FXR）。我们假设影响胆汁酸的特定肠道或当地常驻微生物池和组合物将与表达 FXR 的细胞相互作用以调节 TME 免疫环境。我们报道的是 FXR 高表达的患者首次在 TNBC 中具有更高的无复发生存率亚型，但不是侵袭性较低的管腔 BC 亚型，这表明有针对性的方法的潜力。这该提案的总体目标是测试微生物胆汁酸TNBC 之间的联系机制，这构成了通过微生物组合物产生新疗法和精准医学的机会。我们的创新方法询问我们证明可以改变微生物组的目标微生物途径，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 提高免疫治疗功效从而增强抗肿瘤免疫力。我们将通过执行以下目标来检验我们的假设：1) 确定共生微生物是否在 TNBC 抗肿瘤免疫中发挥生理作用； 2) 确定是否微生物组改变早期肿瘤发病和进展的免疫监视； 3) 确定是否具有药理作用胆汁酸受体激动可改善 TNBC 免疫治疗。所产生的调查结果将产生重大影响，因为 TNBC 缺乏靶向治疗存在巨大的未满足的临床需求，并且可能会带来变革改善患者的治疗效果。