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

摘要 抗肿瘤免疫因天然免疫细胞和获得性免疫细胞、微生物之间的相互作用而不同 群落多样性，宿主和微生物衍生的代谢物，以及其他形成杀瘤作用的局部因素 回应。虽然最近的微生物组研究大多集中在肠道微生物组与癌症 结果，在肿瘤微环境(TME)中检测到肠道外微生物群落。我们 最近报道，与病理正常相比，患者乳腺肿瘤中发现了特定的微生物 乳房样本与肿瘤分期、肿瘤亚型有关，并首次与种族有关。三重负面乳房 癌症(TNBC)，一种侵袭性的亚型，通常无法通过个性化的药物治疗， 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)的疗效。然而，到目前为止，支持这些观察的机制是 关于肠道和/或肠外微生物群如何影响BC的发病、进展和 对治疗的反应，这是该领域的一个主要知识空白。一种令人信服的机制可能会将 微生物对肿瘤的免疫作用是微生物修饰的代谢产物，即胆汁酸。某些富含微生物的 在7-α-羟基酶中，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 已经被证明通过逆转免疫抑制来限制其他癌症的进展和转移， 但很少有工作探索胆汁酸在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)。我们假设影响胆汁酸的特定肠道或本地微生物 池和成分将与表达FXR的细胞相互作用，以调节TME免疫环境。我们的报告是 首次发现高FXR表达的患者在TNBC中有更大的无复发生存率 亚型，但不是在侵袭性较弱的BC亚型中，这表明有可能进行有针对性的治疗。这个 这项提案的总体目标是测试连接微生物胆汁酸TNBC的机制，这构成了一种 利用微生物成分创造新疗法和精准医学的机会。我们的 创新的方法询问我们展示的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，如胆汁酸，通过对TME重新编程来提高免疫治疗效果 从而增强抗肿瘤免疫力。我们将通过执行以下目标来验证我们的假设：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 微生物组改变对早期肿瘤发生和发展的免疫监测；3)确定是否具有药理学意义 胆汁酸受体激动剂可改善TNBC免疫治疗。产生的调查结果将产生很大的影响，因为 缺乏针对TNBC的靶向治疗提供了一个巨大的未得到满足的临床需求，并可能转变为 改善患者的预后。

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.