Role of Gut Microbiota in Modulating Immune Checkpoint Inhibitory Therapy for Cancer

肠道微生物群在调节癌症免疫检查点抑制疗法中的作用

基本信息

批准号：
10738330
负责人：
Jade Homsi
金额：
$ 7.34万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10738330
关键词：
Abdomen Address Adoptive Transfer Adult Advanced Malignant Neoplasm Amino Acid Sequence Antibiotics Antigens Antitumor Response Bacteria Body mass index CD8-Positive T-Lymphocytes Cancer Patient Cells Cellular Assay Clinical Data Diet Disease Progression Disease remission Education Effectiveness Environmental Risk Factor Exposure to Gender Genetic Germ-Free Goals Grant Granzyme Human Human Microbiome Immune Immune checkpoint inhibitor Immune response Immune system Immunology In Vitro Integration Host Factors Interferon Type II Intestines Malignant Neoplasms Metastatic Melanoma Microbiology Modeling Molecular Mus Oral Administration Patients Pre-Clinical Model Probiotics Production Progressive Disease Research Role Sequence Homologs Testing Treatment Efficacy Weight Yogurt adaptive immune response anticancer activity cancer immunotherapy cancer therapy checkpoint therapy draining lymph node gut bacteria gut microbiome gut microbiota human study immune checkpoint immunogenic immunoregulation in vivo individual patient innovation insight melanoma mesenteric lymph node microbial microbiome microbiota microbiota profiles microorganism neoantigens novel novel strategies pre-clinical probiotic therapy programmed cell death protein 1 recruit response translational oncology translational study treatment response tumor

项目摘要

Immune checkpoint inhibitor therapy (ICT) unleashes the immune system resulting in durable remissions in up to 50% of patients with previously incurable cancers, such as metastatic melanoma. But the host factors that modulate or dictate ICT response are poorly understood. Recent, preclinical data suggests that specific gut microbiota are required for optimizing response to ICT. These commensal gut microbiota augment host adaptive immune responses, specifically host immune cells, needed for anti-cancer activity. We recently showed that adult melanoma patients who respond to ICT have a distinct gut microbiota signature compared to patients with progressive disease. In preliminary data, we demonstrated that precision probiotic therapy (using the specific bacteria that we identified in our clinical/translational study) augmented the efficacy of ICT in mice with melanoma whereas a probiotic commonly found in yogurt did not. Microbiota dictated a reduction in PD-1 expressing CD4 and CD8 T cells in mesenteric lymph nodes (MLNs) following ICT. Of note, these specific gut microbiota had a greater number of protein sequences homologous to human melanoma neoantigens when compared to the ineffective yogurt probiotic. Further, these gut microbiota induced CD4 and CD8 T cell production of IFN-gamma and Granzyme B. Interestingly, mice without draining lymph nodes in the gut did not respond to ICT. ICT promoted gut microbiota translocation into MLNs. Finally, oral administration of heat-killed gut microbiota did not augment ICT efficacy, suggesting that live bacteria are required for augmenting ICT. Therefore, our central hypothesis is that only gut microbiota that have both high immunogenic potential and the ability to translocate into the abdominal draining lymph nodes will facilitate activation/education of immune cells and thus augment ICT efficacy. To test this hypothesis, we will pursue the following three specific aims. First, we will further define both gut microbiome and tumor genetic differences in melanoma patients who respond to ICT compared to those with disease progression. Second, we will identify environmental and microbial factors that dictate gut microbiota translocation into mesenteric lymph nodes. Third, we will elucidate the mechanisms by which gut microbiota modulate host immune cell anti-tumor response by performing in vitro functional immune cell assays to determine if and how specific gut microbiota prime immune cells and in vivo studies to identify the specific immune cells recruited by gut microbiota. These studies will lay the groundwork for the following innovations: 1) a novel mechanism by which gut microbiota activate immune defenses against cancer and 2) a novel approach (precision probiotics) for optimizing ICT efficacy in advanced cancer patients.

免疫检查点抑制剂疗法 (ICT) 释放免疫系统，从而实现持久缓解 50% 的患者患有先前无法治愈的癌症，例如转移性黑色素瘤。但主办方认为人们对调节或指示 ICT 响应知之甚少。最近的临床前数据表明，特定的肠道优化对 ICT 的响应需要微生物群。这些共生肠道微生物群增强了宿主抗癌活性所需的适应性免疫反应，特别是宿主免疫细胞。我们最近研究表明，与其他人相比，对 ICT 有反应的成年黑色素瘤患者具有独特的肠道微生物群特征疾病进展的患者。在初步数据中，我们证明了精准益生菌疗法（使用我们在临床/转化研究中发现的特定细菌）增强了 ICT 对小鼠的功效与黑色素瘤有关，而酸奶中常见的益生菌则不会。微生物群导致 PD-1 减少 ICT 后肠系膜淋巴结 (MLN) 中表达 CD4 和 CD8 T 细胞。值得注意的是，这些特定的肠道当微生物群具有大量与人类黑色素瘤新抗原同源的蛋白质序列时与无效的酸奶益生菌相比。此外，这些肠道微生物群诱导 CD4 和 CD8 T 细胞 IFN-γ 和粒酶 B 的产生。有趣的是，没有引流肠道淋巴结的小鼠没有响应信息通信技术。 ICT 促进肠道微生物群易位至 MLN。最后口服热灭活剂肠道微生物群并没有增强 ICT 功效，这表明增强 ICT 需要活细菌。因此，我们的中心假设是，只有肠道微生物群既具有高免疫原性潜力，又具有转移到腹部引流淋巴结的能力将促进免疫细胞的激活/教育从而提高 ICT 的效率。为了检验这一假设，我们将追求以下三个具体目标。第一的，我们将进一步定义对以下药物有反应的黑色素瘤患者的肠道微生物组和肿瘤遗传差异： ICT 与疾病进展的患者进行比较。其次，我们将确定环境和微生物因素这决定了肠道微生物群易位到肠系膜淋巴结。三、阐明机制肠道微生物群通过执行体外功能来调节宿主免疫细胞的抗肿瘤反应免疫细胞测定以确定特定肠道微生物群是否以及如何启动免疫细胞以及体内研究识别肠道微生物群招募的特定免疫细胞。这些研究将为以下创新：1）肠道微生物群激活抗癌免疫防御的新机制 2) 一种优化晚期癌症患者 ICT 疗效的新方法（精准益生菌）。