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

益生菌罗伊氏乳杆菌在协调全身抗肿瘤免疫中的作用

基本信息

批准号：
10417677
负责人：
Marlies Meisel
金额：
$ 17.39万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-07 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417677
关键词：
Affect Agonist Antigen-Presenting Cells Aromatic Amino Acids Aryl Hydrocarbon Receptor Bacteria Bacterial Translocation CD8-Positive T-Lymphocytes CD8B1 gene Chemopreventive Agent Clinical Colon Carcinoma Complex Data Disease Distal Effector Cell Functional disorder Goals Granzyme Health Health Promotion Human Immune Immune checkpoint inhibitor Immunity Incidence Indoles Inflammatory Interferons Intestines Knowledge Lactobacillus Lactobacillus reuteri Ligands Maintenance Malignant Neoplasms Mediating Microbe Modeling Mucous Membrane Mus Myelogenous Myeloproliferative disease Oral Outcome PPBP gene Patients Play Probiotics Receptor Signaling Research Resistance Risk Factors Role Secondary to Signal Transduction T cell differentiation T-Lymphocyte TC1 Cell Techniques Testing Therapeutic Traction Transaminases Treatment Efficacy Tryptophan Tumor Immunity United States Ursidae Family adaptive immunity anti-PD-L1 anti-cancer anti-tumor immune response aryl hydrocarbon receptor ligand base cancer immunotherapy cell mediated immune response checkpoint therapy commensal bacteria cytotoxic dietary dysbiosis global health gut bacteria gut microbes gut microbiome gut microbiota health economics immune checkpoint blockade immunoregulation improved intestinal barrier melanoma microbial microbiome microbiota mouse model neoplastic cell next generation sequencing novel programmed cell death ligand 1 programmed cell death protein 1 secondary lymphoid organ spatiotemporal success therapy outcome tool tumor tumorigenic

项目摘要

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.

项目概要肠道微生物组对健康和复杂疾病的系统免疫产生深远影响，例如作为癌症。大量研究强调了肠道微生物组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 CD8 T 细胞（Tc1 细胞）发挥着通过有效杀死肿瘤细胞并影响免疫检查点，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）被用来促进健康已有多年世纪以来，作为小鼠癌症免疫治疗成功的关键组成部分而受到关注人类。然而，益生菌如何协调全身抗肿瘤免疫和调节癌症免疫治疗结果仍不完全清楚。罗伊氏乳杆菌 (L. reuteri) 是最常用的益生菌之一，在结肠癌中发挥有益作用。然而，罗伊氏乳杆菌的作用 Tc1 调节全身抗肿瘤免疫的作用仍不清楚。肠道微生物群起着基础作用在维持肠道屏障完整性和破坏肠道微生物群落（菌群失调）中的作用构成多种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有关包括癌症。我们最近发现肠道细菌易位是由微生物介导的肠道屏障功能障碍导致骨髓癌小鼠模型中白血病前期骨髓恶性肿瘤的发生。在肠道和全身肿瘤中发现了微生物信号，这些信号既可以促进肿瘤的生长，也可以起到抗肿瘤的作用。致瘤功能。然而，系统性肿瘤中存在存活的肠道细菌及其潜在的肿瘤内在微生物如何影响肿瘤免疫的机制仍不明确。我们的初步数据表明口服罗伊氏乳杆菌可促进荷黑色素瘤小鼠的全身 Tc1 细胞免疫，并且与活的罗伊氏乳杆菌从肠道短暂传播到次级淋巴器官有关和黑色素瘤。此外，我们有初步迹象表明黑色素瘤的形成会诱导肠道屏障功能障碍，这表明口服罗伊氏乳杆菌到达肠道远端的可能机制黑色素瘤。基于肠道微生物对系统影响的有据可查的发现黑色素瘤，结合我们的初步数据，我们的总体假设是益生菌罗伊氏乳杆菌通过介导全身抗肿瘤 Tc1 细胞免疫并促进黑色素瘤的癌症免疫治疗 (AIM 1) 活的罗伊氏乳杆菌从肠道易位至肠道远端黑色素瘤肿瘤（AIM 2）。我们将测试这个假设并剖析罗伊氏乳杆菌如何调节抗癌免疫和意志的潜在机制定义罗伊氏乳杆菌如何进入肠道远端肿瘤的机制。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症。