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

项目摘要 肠道微生物组对健康和复杂疾病中的全身免疫产生深远影响， 癌症许多研究强调了肠道微生物组调节癌症的强大抗癌能力， 肠外（全身）抗肿瘤免疫。产生细胞毒性干扰素-g的CD 8 T细胞（Tc 1细胞）发挥了重要作用。 通过有效杀死肿瘤细胞和影响免疫检查点，在介导抗肿瘤免疫中发挥核心作用 封锁疗法细菌补充剂（益生菌）已被用于促进健康超过一个世纪。 世纪以来，它作为小鼠和小鼠成功癌症免疫治疗的关键组成部分越来越受到关注 人类然而，益生菌如何协调系统性抗肿瘤免疫和 调节癌症免疫治疗结果仍然不完全清楚。罗伊氏乳杆菌（Lactobacillus reuteri）。reuteri）是 最常用的益生菌之一，在结肠癌中发挥有益作用。然而，L.罗伊氏 在调节系统性抗肿瘤Tc 1免疫中的作用仍不明确。肠道微生物群是 在维持肠道屏障完整性和破坏肠道微生物群落（生态失调）中的作用 构成了几种形式的肠癌和非肠癌的主要危险因素。此外，肠 屏障功能障碍和肠道细菌移位与复杂的炎症性疾病有关 包括癌症我们最近发现，由微生物群介导的肠道细菌移位 肠屏障功能障碍驱动骨髓癌小鼠模型中的白血病前期骨髓恶性肿瘤。 在肠道和全身性肿瘤中发现了微生物信号，这些信号既可促进肿瘤的生长，也可抑制肿瘤的生长。 致瘤功能然而，在全身性肿瘤中存在活的肠道细菌和潜在的 肿瘤固有微生物如何影响肿瘤免疫的机制仍不清楚。我们的初步数据 提示灌胃L. reuteri驱动黑色素瘤荷瘤小鼠的全身Tc 1细胞免疫， 与活的L.从肠到次级淋巴器官 和黑色素瘤。此外，我们有初步迹象表明，黑色素瘤的形成诱导肠道 屏障功能障碍，这表明口服灌胃L. reuteri可以到达肠道远端 黑素瘤基于有据可查的肠道微生物对全身影响的研究结果， 黑色素瘤，连同我们的初步数据，我们的总体假设是，益生菌L。罗伊氏 介导全身性抗肿瘤Tc 1细胞免疫，并通过以下方式促进黑色素瘤（AIM 1）的癌症免疫治疗： 活菌L. reuteri从肠道到肠道远端黑色素瘤（AIM 2）。我们将测试这个 假设并剖析了L. reuteri调节抗癌免疫力， 定义了L. reuteri获得进入肠道远端肿瘤的机会。该提案的长期目标是 提供合理的方法，通过调节肠道微生物群来控制全身肿瘤免疫， 癌

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.