Employing Humanized Microbiome Mice to Understand Immune Activation and Translational Therapeutic Potential in Glioblastoma

利用人源化微生物组小鼠来了解胶质母细胞瘤的免疫激活和转化治疗潜力

• 批准号: 10665439
• 负责人: Braden Cox McFarland
• 金额: $ 32.93万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665439
• 关键词: Address; Affect; Anti-CD47; Behavior Therapy; Bone Marrow; CD47 gene; CSF1R gene; Cancer Model; Cell Surface Proteins; Cells; Colon Carcinoma; Communities; Environment; Glioblastoma; Human; Human Microbiome; Immune; Immune Targeting; Immune checkpoint inhibitor; Immunologics; Immunotherapy; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Laboratory mice; Link; Macrophage; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Microbe; Microglia; Modeling; Mus; Patients; Phagocytosis; Pharmaceutical Preparations; Phenotype; Population; Pre-Clinical Model; Probiotics; Publishing; Reporting; Resistance; Role; Signal Transduction; T cell infiltration; T-Cell Activation; T-Lymphocyte; Target Populations; Testing; Therapeutic; Therapeutic Uses; Tumor-associated macrophages; Work; anti-PD-1; anti-tumor immune response; antitumor effect; beneficial microorganism; fecal transplantation; gut bacteria; gut microbiome; gut microbiota; human microbiota; immune activation; immune cell infiltrate; inflammatory milieu; inhibitor; melanoma; microbial; microbial community; microbiome; microbiome alteration; microbiome composition; microorganism interaction; mouse model; neoplastic cell; novel; pre-clinical; probiotic therapy; public health relevance; response; targeted treatment; therapy resistant; translational potential; translational therapeutics; tumor

PROJECT SUMMARY The composition of the gut microbiome has been shown to determine responsiveness or resistance to immune checkpoint inhibitors (ICI), such as anti-PD-1, in patients with melanoma and other cancers. Unfortunately, although immunotherapy works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has not demonstrated efficacy in humans. Most pre-clinical cancer studies have been done in mouse models using mouse gut microbiomes, but there are significant differences between mouse and human microbial gut compositions. To address this anomaly, we developed a novel humanized microbiome (HuM) model to study the response to immunotherapy in a pre-clinical mouse model of GBM. We have recently published that various human microbiome compositions can dictate the efficacy of T-cell ICIs (anti-PD-1) in a pre-clinical GBM model. We are the first to report that human microbiota affects T-cell ICI response in mouse models of GBM, indicating that for patients with GBM, there may be beneficial microbes that can increase efficacy of ICIs. Furthermore, the largest portion of immune cells in GBM are tumor associated macrophages and microglia (TAMs). To date, no studies have examined the role of the microbiome in response to TAM targeted therapies, such as CSF1R inhibition or anti-CD47, in GBM. In addition, the question still remains of whether the “responsive” microbial communities in can be therapeutically exploited to rescue resistance to therapies, or if the “resistant” microbial communities in can be depleted and/or replaced. We have identified “responder” or optimal human microbiome compositions, as well as “non-responder” or resistant human microbiome compositions in our pre-clinical GBM models, which have also been confirmed in a melanoma model. We hypothesize that responder microbiome communities promote a heightened baseline level of anti-tumor inflammation, which helps stimulate the efficacy of immunotherapy in GBM. Using our novel humanized microbiome mouse model, this proposal seeks to uncover the human microbial- immune mechanisms of response to immunotherapies in GBM pre-clinical models, including T-cell (Aim 1) and TAM (Aim 2) mediated effects, and assess if responder microbiomes can be exploited and used therapeutically. Overall, we seek to enhance our understanding of the role of human microbiota in innate and adaptive immune-microbial interactions, and to demonstrate the translational potential of responder “optimal” microbiomes.

项目概要 肠道微生物组的组成已被证明可以决定对细菌的反应或抵抗 不幸的是，免疫检查点抑制剂（ICI），例如抗 PD-1，可用于治疗黑色素瘤和其他癌症患者。 尽管免疫疗法在胶质母细胞瘤（GBM）临床前小鼠模型中效果良好，但该疗法并没有 大多数临床前癌症研究都是在小鼠模型中进行的。 小鼠肠道微生物组，但小鼠和人类肠道微生物组之间存在显着差异 为了解决这一异常现象，我们开发了一种新型人源化微生物组（HuM）模型来研究。 我们最近发表了各种关于 GBM 临床前小鼠模型对免疫治疗的反应。 人类微生物组成分可以决定 T 细胞 ICI（抗 PD-1）在临床前 GBM 中的功效 我们是第一个报告人类微生物群影响 GBM 小鼠模型中 T 细胞 ICI 反应的研究。 表明对于 GBM 患者，可能存在可以提高 ICI 疗效的有益微生物。 此外，GBM 中免疫细胞的最大部分是肿瘤相关巨噬细胞和小胶质细胞 (TAM) 迄今为止，还没有研究检验微生物组对 TAM 靶向治疗的作用。 例如CSF1R抑制或抗CD47，在GBM中是否“有反应”仍然是一个问题。 可以在治疗上利用微生物群落来挽救对治疗的耐药性，或者如果“耐药” 中的微生物群落可能被耗尽和/或被替换。 我们已经确定了“反应者”或最佳人类微生物组组成，以及“无反应者”或 我们的临床前 GBM 模型中存在耐药性人类微生物组成分，这也在一项研究中得到了证实 我们勇敢地承认，反应者微生物群落促进了肿胀。 抗肿瘤炎症的基线水平，有助于刺激 GBM 免疫治疗的疗效。 使用我们新颖的人源化微生物组小鼠模型，该提案旨在揭示人类微生物- GBM 临床前模型（包括 T 细胞）对免疫疗法反应的免疫机制（Aim 1) 和 TAM（目标 2）介导的效应，并评估是否可以利用和使用反应者微生物组 总体而言，我们寻求增强对人类微生物群在先天和中的作用的理解。 适应性免疫-微生物相互作用，并证明反应者“最佳”的转化潜力 微生物组。