Improvement of cellular immunotherapy during dysbiosis- Resubmission

生态失调期间细胞免疫疗法的改进-重新提交

• 批准号: 10680445
• 负责人: Ruud P.M. Dings
• 金额: $ 34.32万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680445
• 关键词: Acceleration; Affect; Ampicillin; Antibiotic Therapy; Antibiotics; Blood Vessels; Cancer Patient; Cell Adhesion Molecules; Cellular immunotherapy; Ciprofloxacin; Clinic; Clinical; Congenic Mice; Data; Defect; Development; Distal; Dorsal; Effectiveness; Endothelial Cells; Endothelium; Extravasation; Flow Cytometry; Fluorescence Microscopy; Foundations; Frequencies; Future; Gastrointestinal tract structure; Goals; Homeostasis; Human; Image; Immune; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapy; Incidence; Infection; Intercellular adhesion molecule 1; Investigational Therapies; Knowledge; Leukocyte Trafficking; Leukocytes; MEL Gene; Malignant Neoplasms; Metronidazole; Modeling; Molecular; Morbidity - disease rate; Mus; Neomycin; Nude Mice; Patients; Publishing; Solid Neoplasm; Supplementation; T cell infiltration; T cell therapy; T-Lymphocyte; TNF gene; Therapeutic; Time; Treatment Efficacy; Trimethoprim-Sulfamethoxazole; Tumor Immunity; Tumor Suppression; Vancomycin; Work; chimeric antigen receptor T cells; combat; commensal bacteria; dysbiosis; effector T cell; fecal transplantation; fighting; gut microbiome; gut microbiota; immunogenic; improved; intravital microscopy; melanoma; microbiome; optoacoustic tomography; pathogenic bacteria; rRNA Genes; response; success; therapy development; trafficking; transcriptome sequencing; tumor; tumor microenvironment; tumor progression; unpublished works

Summary/Abstract The use of antibiotics has significantly increased in recent years. Antibiotics (ABX) severely alter the gut microbiome, destroying potentially pathogenic bacteria, as well as beneficial ones—producing a state of microbial imbalance called dysbiosis. Notably, a diminished gut microbiome has severe defects on the immune system, yet how these defects may affect cellular immunotherapy is largely unknown. To better understand how dysbiosis influences cellular immunotherapy, we focused on melanoma as an exemplary immunogenic solid tumor. The incidence of melanoma has increased drastically over the past decades, with its morbidity rate continuing to outpace that of most other cancers. Early stages of melanoma are often successfully controlled and treated; yet patients with advanced stages of melanoma are treated with cellular immunotherapy and only 50% respond. We hypothesize that ABX-induced dysbiosis dictates, at least in part, the reduction in treatment efficacy. Our overall goal is to define the systemic effects of antibiotic-induced dysbiosis on the distal tumor microenvironment and develop therapies to promote antitumor immunity. The major objective of this application is to overcome dysbiosis-induced ICAM-1 suppression and thereby enhance the effectiveness of cellular immunotherapy. Attaining this objective will be the next step in increasing the efficacy and response rate of immunotherapies. We formulated a robust and unbiased approach using various melanoma models to accomplish the following Aims: Aim 1. Identify ABX primarily responsible for stromal immune suppression resulting in tumor progression. Aim 2. Increase ICAM-1 on tumor-associated endothelial cells during dysbiosis. Aim 3. Increase cellular immunotherapy efficacy in melanoma during dysbiosis. Completing these aims will expand our understanding on how antibiotics-induced perturbation of the gut microbiome impacts the distal tumor microenvironment. This work has the potential to establish new paradigms aimed at enhancing the efficacy and response rate of immunotherapies by modulating the tumor vasculature, as all types of immunotherapy ultimately dependent on efficient trafficking of effector leukocytes into the tumor.

总结/摘要 近年来，抗生素的使用显著增加。抗生素（ABX）严重改变了 肠道微生物组，破坏潜在的致病细菌，以及有益的，生产一个 微生物的不平衡状态称为生态失调。值得注意的是，减少的肠道微生物组对肠道微生物的生长有严重的缺陷。 然而，这些缺陷如何影响细胞免疫疗法在很大程度上是未知的。 为了更好地了解生态失调如何影响细胞免疫治疗，我们将重点放在黑色素瘤上， 示例性免疫原性实体瘤。黑色素瘤的发病率在20世纪90年代急剧上升， 在过去的几十年里，它的发病率继续超过大多数其他癌症。初期 黑色素瘤通常被成功地控制和治疗;然而患有晚期黑色素瘤的患者， 用细胞免疫疗法治疗，只有50%有反应。我们假设ABX引起的生态失调 至少部分地指示治疗功效的降低。 我们的总体目标是确定抗生素诱导的微生态失调对远端 肿瘤微环境和开发疗法，以促进抗肿瘤免疫。主要 本申请的目的是克服生态失调诱导的ICAM-1抑制， 细胞免疫疗法的有效性实现这一目标将是提高妇女地位的下一步。 免疫疗法的疗效和应答率。我们制定了一个强大的和公正的方法， 各种黑色素瘤模型，以实现以下目的： 目标1.确定ABX主要负责导致肿瘤进展的基质免疫抑制。 目标2.在微生态失调期间增加肿瘤相关内皮细胞上的ICAM-1。 目标3.在生态失调期间增加黑色素瘤的细胞免疫治疗功效。 完成这些目标将扩大我们的理解，如何南极引起的扰动的 肠道微生物组影响远端肿瘤微环境。这项工作有可能建立新的 旨在通过调节免疫调节剂来增强免疫疗法的功效和应答率的范例 由于所有类型的免疫治疗最终依赖于效应物的有效运输， 白细胞进入肿瘤