Role of probiotic Lactobacillus reuteri in orchestrating systemic anti-tumor immunity

项目摘要 肠道微生物群对健康和复杂疾病中的系统免疫有深远的影响，如 就像癌症一样。大量研究强调了肠道微生物群调节的强大抗癌能力 肠外(全身)抗肿瘤免疫。产生细胞毒性干扰素-g的CD8T细胞(Tc1细胞)发挥作用 杀伤肿瘤细胞和影响免疫检查点在介导抗肿瘤免疫中的中心作用 封锁疗法。细菌补充剂(益生菌)用于促进健康已有一年多的历史。 作为成功的小鼠和小鼠癌症免疫治疗的关键组成部分， 人类。然而，益生菌如何协调全身抗肿瘤免疫和 调节肿瘤免疫治疗结果的机制仍不完全清楚。鲁氏乳杆菌(L.reuri)是 益生菌是最常用的益生菌之一，对结肠癌有好处。然而，L.reuri的作用 在调节全身性抗肿瘤方面，Tc1免疫功能仍不明确。肠道微生物区系起着基本的作用 在维持肠道屏障完整性和破坏肠道微生物群落(生物失调)方面的作用 构成了几种形式的肠道和非肠道癌症的主要危险因素。此外，肠道 屏障功能障碍和肠道细菌易位与复杂的炎症性疾病相关 包括癌症。我们最近发现，肠道细菌易位是由微生物区系介导的 肠屏障功能障碍在髓系癌小鼠模型中导致白血病前期髓系恶性肿瘤。 在肠道和全身肿瘤中发现了微生物信号，这些信号既有支持的，也有反对的。 具有致癌功能。然而，系统性肿瘤中肠道活细菌的存在及其潜在的 肿瘤内生微生物如何影响肿瘤免疫的机制尚不清楚。我们的初步数据 提示口服罗氏乳杆菌可提高荷瘤小鼠的Tc1细胞免疫功能。 与活的罗伊氏杆菌从肠道向次级淋巴器官的瞬时传播有关 和黑色素瘤。此外，我们有初步的迹象表明，黑色素瘤的形成会导致肠道 屏障功能障碍，这表明了一种可能的机制，即口服罗氏杆菌可以到达肠道末端 黑色素瘤。基于有充分记录的肠道微生物对全身的影响 黑色素瘤，连同我们的初步数据，我们的首要假设是益生菌L.reuri 介导全身性抗肿瘤Tc1细胞免疫并促进黑色素瘤肿瘤免疫治疗(AIM-1) 活的罗伊氏杆菌从肠道转移到肠道远端黑色素瘤(目标2)。我们将对此进行测试 假设并剖析罗氏乳杆菌调节抗癌免疫的潜在机制 明确路氏乳杆菌如何获得肠道远端肿瘤的机制。这项提议的长期目标是 通过调节肠道微生物区系，为控制全身肿瘤免疫提供合理的方法 癌症。

Project Summary The gut microbiome exerts a profound impact on systemic immunity in health and in complex diseases, such as cancer. Numerous studies highlighted the robust anti-carcinogenic ability of the gut microbiome to regulate extra-intestinal (systemic) anti-tumor immunity. Cytotoxic interferon-g producing CD8 T cells (Tc1 cells) play a central role in mediating anti-tumor immunity by potently killing tumor cells and affecting immune checkpoint blockade therapies. Bacterial supplements (probiotics) have been used to promote health for more than a century and are gaining traction as a crucial component in successful cancer immunotherapy in mice and humans. Yet, the underlying mechanisms how probiotics orchestrate systemic anti-tumor immunity and modulate cancer immunotherapy outcome remain incompletely understood. Lactobacillus reuteri (L. reuteri) is one of the most frequently used probiotics and plays a beneficial role in colon cancer. Yet, the role of L. reuteri in modulating systemic anti-tumor Tc1 immunity remains undefined. The gut microbiota plays a fundamental role in the maintenance of intestinal barrier integrity and disruption of the gut microbial community (dysbiosis) constitutes a major risk factor for several forms of intestinal and non-intestinal cancers. Moreover, intestinal barrier dysfunction and gut bacterial translocation are associated with complex inflammatory diseases including cancer. We recently showed that gut bacterial translocation resulting from microbiota-mediated intestinal barrier dysfunction drives preleukemic myeloid malignancy in a mouse model of myeloid cancer. Microbial signals were identified in intestinal as well as systemic tumors, which serve both pro- and anti- tumorigenic functions. However, the presence of viable gut bacteria in systemic tumors and the underlying mechanisms how tumor intrinsic microbes affect tumor immunity remain ill defined. Our preliminary data suggest that orally gavaged L. reuteri drives systemic Tc1 cell immunity in melanoma tumor bearing mice and is associated with transient dissemination of viable L. reuteri from the intestine to secondary lymphoid organs and melanoma tumors. Moreover, we have preliminary indications that melanoma tumor-formation induces gut barrier dysfunction, which suggests a possible mechanism how orally gavaged L. reuteri can reach gut-distal melanoma tumors. Based on well documented findings of the systemic impact of gut microbes during melanoma, together with our preliminary data, our overarching hypothesis is that the probiotic L. reuteri mediates systemic anti-tumor Tc1 cell immunity and facilitates cancer immunotherapy in melanoma (AIM 1) by translocation of viable L. reuteri from the gut to gut-distal melanoma tumors (AIM 2). We will test this hypothesis and dissect the underlying mechanisms how L. reuteri modulates anti-cancer immunity and will define the mechanisms how L. reuteri gains access to gut-distal tumors. The long-term goal of this proposal is to provide rational approaches to control systemic tumor immunity by modulating the gut microbiota during cancer.