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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：
9815255
负责人：
Jade Homsi
金额：
$ 62.71万
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/9815255
关键词：
Abdomen Address Adoptive Transfer Adult Advanced Malignant Neoplasm Amino Acid Sequence Antibiotics Antigens Antitumor Response Bacteria CD8-Positive T-Lymphocytes Cancer Patient Cells Cellular Assay Clinical Data Diet Disease Progression Disease remission Education Effectiveness Environmental Risk Factor Exposure to Fibrinogen Gender Genetic 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 Mesentery Metastatic Melanoma Microbiology Modeling Molecular Mus Oral Administration Patients Pre-Clinical Model Probiotics Production Progressive Disease Research Role SLEB2 gene Sequence Homologs Testing Treatment Efficacy Weight Yogurt adaptive immune response anticancer activity cancer immunotherapy cancer therapy checkpoint therapy gut bacteria gut microbiome gut microbiota human study immune checkpoint immunogenic in vivo individual patient innovation insight lymph nodes melanoma microbial microbiome microbiota microbiota profiles microorganism neoantigens novel novel strategies oncology pre-clinical probiotic therapy recruit response translational study 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.

免疫检查点抑制疗法(ICT)释放免疫系统，导致UP持久缓解到50%患有转移性黑色素瘤等以前无法治愈的癌症的患者。但寄主因素是人们对信息和通信技术反应的调节或支配知之甚少。最近的临床前数据表明，特定的肠道微生物区系是优化对信息和通信技术的反应所必需的。这些共生的肠道微生物群增加了宿主适应性免疫反应，特别是宿主免疫细胞，是抗癌活动所必需的。我们最近显示对ICT有反应的成年黑色素瘤患者具有明显的肠道微生物群特征进展性疾病的患者。在初步数据中，我们证明了精密益生菌疗法(使用我们在临床/翻译研究中确定的特定细菌)增强了ICT对小鼠的疗效与黑色素瘤有关，而酸奶中常见的益生菌则没有。微生物区系决定了PD-1的减少 ICT术后肠系膜淋巴结中CD4和CD8 T细胞的表达值得注意的是，这些特殊的直觉当微生物群具有更多与人黑色素瘤新抗原同源的蛋白质序列时与无效的酸奶相比，益生菌。此外，这些肠道微生物群诱导了CD4和CD8T细胞产生干扰素-γ和颗粒酶B。有趣的是，没有肠道淋巴引流的小鼠不会应对信息和通信技术。ICT促进肠道微生物区系向MLN的移位。最后，口服中暑致死药肠道微生物区系没有增强ICT的功效，这表明活细菌是增强ICT所必需的。因此，我们的中心假设是，只有同时具有高免疫原性潜力和移位到腹部引流淋巴结的能力将促进免疫细胞的激活/教育从而增强信息和通信技术的功效。为了验证这一假设，我们将追求以下三个具体目标。第一, 我们将进一步确定肠道微生物组和肿瘤遗传差异在黑色素瘤患者谁对信息和通信技术与那些疾病进展的人相比。第二，我们将确定环境和微生物因素这决定了肠道微生物区系移位到肠系膜淋巴结。第三，我们将阐明这些机制肠道微生物区系通过执行体外功能调节宿主免疫细胞抗肿瘤反应免疫细胞分析以确定特定的肠道微生物区系是否以及如何启动免疫细胞和体内研究确定肠道微生物区系招募的特定免疫细胞。这些研究将为以下创新：1)肠道微生物区系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(精密益生菌)。