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

总结 抗肿瘤免疫由于先天免疫细胞和适应性免疫细胞、微生物免疫细胞和细胞因子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形成杀肿瘤作用的局部因素 应答虽然最近的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，与病理正常相比， 乳腺样本与肿瘤分期、肿瘤亚型相关，并首次与种族相关。三阴性乳腺 癌症（TNBC）是一种侵袭性亚型，通常无法采用个性化药物治疗， 含有可能介导免疫抑制并影响标准化疗的独特微生物， 免疫检查点抑制剂（ICI）功效。然而，迄今为止，支持这些意见的机制是 关于肠道和/或肠外微生物组如何影响BC发作、进展和 对治疗的反应，这是该领域的一个主要知识空白。一个有说服力的机制， 抗肿瘤免疫的微生物是微生物修饰的代谢物，即胆汁酸。某些微生物丰富 在7-α-羟化酶中，将初级胆汁酸转化为次级胆汁酸，其调节胆汁酸组成。胆汁酸 已经显示通过逆转免疫抑制来限制其他癌症的进展和转移， 但很少有研究探讨胆汁酸在BC中的作用。胆汁酸通过几种胆汁酸受体传递信号 包括法尼醇X受体（FXR）。我们认为，特定的肠道或当地居民的微生物，影响胆汁酸 库和组合物将与表达FXR的细胞相互作用以调节TME免疫环境。我们报告 首次发现FXR高表达的患者在TNBC中具有更高的无复发生存率， 亚型，但不是在侵略性较低的管腔BC亚型，这表明靶向方法的潜力。的 该提案的总体目标是测试微生物胆汁酸与TNBC之间的联系机制， 通过微生物组成产生新的治疗方法和精确药物的机会。我们 创新的方法询问我们证明改变微生物组的靶向微生物途径， 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，如胆汁酸，通过重编程TME增加免疫功效， 导致增强的抗肿瘤免疫力。我们将通过执行以下目标来测试我们的假设：1） 确定肠道微生物是否在TNBC抗肿瘤免疫中起生理作用; 2）确定肠道微生物是否在TNBC抗肿瘤免疫中起生理作用; 微生物组改变了早期肿瘤发病和进展的免疫监视; 3）确定是否有药理学 胆汁酸受体激动改善TNBC免疫疗法。产生的结果将产生很大的影响，因为 缺乏针对TNBC的靶向治疗提出了很大的未满足的临床需求，并且可能会改变 改善患者预后。

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.