Role of the gut microbiome in modulating the efficacy of checkpoint blockade therapy

肠道微生物组在调节检查点阻断疗法疗效中的作用

基本信息

批准号：
10057372
负责人：
Vyara Matson
金额：
$ 7.26万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057372
关键词：
Aerobic Agar Anaerobic Bacteria Bacteria Biological Models Cancer Patient Cells Chemosensitization Clinic Clinical Culture Media Data Development Distant Feces Formulation Future Genetic Polymorphism Germ-Free Goals Growth Gut Mucosa Human Immune Immunotherapeutic agent Immunotherapy Intrinsic factor Lead Link Malignant Neoplasms Mediating Modeling Mus Oncogenes Outcome PD-1 blockade Pathway interactions Patients Pharmacology Preparation Probiotics Property Regimen Regulator Genes Research Role Sampling Science Site Source T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Travel Treatment outcome Tumor Immunity Tumor-infiltrating immune cells Work anti-PD-1 anti-PD-L1 anti-tumor immune response antitumor effect base commensal bacteria commensal microbes drug development experimental study genome sequencing gut bacteria gut microbiome gut microbiota human microbiota immune checkpoint blockade immunoregulation improved improved outcome in vivo melanoma microbiome microbiota neoplasm immunotherapy novel strategies patient subsets predictive marker recruit resistance mechanism responders and non-responders response synthetic drug therapy resistant treatment response tumor tumor microenvironment

项目摘要

Project Summary The implementation of checkpoint blockade immunotherapy is having a major impact on cancer outcomes. However, a sizable subset of patients still fails to benefit, and prior research has shown that inadequate baseline T cell infiltration into the tumor microenvironment is associated with lack of clinical response. These findings point to poor spontaneous T cell activation and recruitment as a general mechanism of resistance and motivate the search for mechanisms that regulate the degree of T cell infiltration into the tumor microenvironment. Our group has previously identified tumor- intrinsic oncogene pathways as key variables that contribute to poor T cell recruitment and therapeutic resistance. Host-intrinsic factors such as germline polymorphisms in immune regulatory genes can also influence the degree of T cell infiltration. But in addition, a major environmentally-influenced variable has recently emerged, which is the composition of the commensal microbiota. Recent work in our group has identified the commensal microbiota as a key determinant of anti-tumor immunity and immunotherapy efficacy in a mouse melanoma model (Sivan et al. Science 2015). Based on that work, we pursued a similar correlation in human melanoma patients undergoing anti-PD-1 immunotherapy and found a profound correlation between baseline microbiota composition and clinical response, which was a significant biomarker for predicting treatment outcome (Matson et al. Science 2015). We further demonstrated a deeper causal link by colonizing germ-free mice with responder or non- responder patient microbiomes, which recapitulated the strong or poor therapeutic response to PD-1 blockade, which correlated with the degree of spontanaoues T cell priming against the tumor. In the current proposal, we will employ this model system to further pursue the mechanisms by which the commensal microbiota from humans modulates the anti-tumor immune response in vivo. A major goal is to identify the gut microbiota-driven messenger(s) capable of transmitting the immunomodulatory effect to the tumor site. Understanding these deeper mechanisms of immune potentiation could enable development of drugs that mimic the presence of immune-potentiating bacteria. Another major goal is to isolate and culture the human-derived commensal bacteria with immune-potentiating properties. This effort could lead to the development of probiotics to supplement immunotherapy regimens and improve outcomes in the future.

项目摘要检查点封锁免疫疗法的实施是一个主要对癌症结局的影响。但是，大量患者仍然无法受益，先前的研究表明，基线T细胞浸润不足微环境与缺乏临床反应有关。这些发现指的是自发性T细胞激活和募集不良，作为一般机制阻力并激励寻找调节T细胞程度的机制浸润到肿瘤微环境中。我们的小组以前已经确定了肿瘤固有的致癌基因途径是导致T细胞招募不良的关键变量和治疗性抗性。宿主中的因素，例如种系多态性免疫调节基因也会影响T细胞浸润的程度。但是在此外，最近出现了一个由环境影响的主要变量共生微生物群的组成。我们小组的最新工作已经确定共生微生物群是抗肿瘤免疫力的关键决定因素和小鼠黑色素瘤模型中的免疫疗法功效（Sivan等，Science 2015）。基于这项工作，我们在人黑色素瘤患者中追求类似的相关性接受抗PD-1免疫疗法，发现基线菌群组成和临床反应，这是重要的预测治疗结果的生物标志物（Matson等，Science 2015）。我们进一步通过用响应者或非 - 响应者患者微生物组，概括了强或差治疗对PD-1封锁的响应与Spontanaoues T细胞的程度相关针对肿瘤启动。在当前的建议中，我们将采用此模型系统进一步追求人类的共生微生物群的机制调节体内抗肿瘤免疫反应。一个主要目标是确定肠道微生物群驱动的使者能够将免疫调节作用传输到肿瘤部位。了解这些更深的免疫增强机制可能能够开发模仿免疫抑制细菌的药物。另一个主要目标是隔离和培养人类衍生的共生细菌免疫态度的特性。这种努力可能导致益生菌的发展补充免疫疗法方案并改善未来的预后。