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

项目总结 肠道微生物群的组成已被证明决定了对 免疫检查点抑制物(ICI)，如抗PD-1，用于黑色素瘤和其他癌症患者。不幸的是， 虽然免疫疗法在胶质母细胞瘤(GBM)临床前小鼠模型中效果良好，但该疗法并不奏效。 在人类身上证明了有效性。大多数临床前癌症研究都是在小鼠模型上进行的 小鼠肠道微生物区系，但小鼠肠道微生物与人肠道微生物有显著差异 作文。为了解决这种异常，我们开发了一种新的人源化微生物组(HUM)模型来研究 临床前GBM小鼠模型对免疫治疗的反应。我们最近发表了各种 人类微生物组组成可以决定T细胞ICIS(抗PD-1)在临床前GBM中的疗效 模特。我们首次报道了人类微生物区系影响GBM小鼠模型的T细胞ICI反应， 这表明对于GBM患者，可能存在有益的微生物可以提高ICIS的疗效。 此外，基底膜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。 (TAMS)。到目前为止，还没有研究检查微生物组在靶向治疗中的作用。 如CSF1R抑制或抗CD47。此外，仍然存在的问题是，“响应性” 微生物群落可以在治疗上被利用来挽救对治疗的耐药性，或者如果“耐药性” 中的微生物群落可能会枯竭和/或被取代。 我们已经确定了“响应者”或最佳的人类微生物组组成，以及“非响应者”或 在我们的临床前GBM模型中具有耐药性的人类微生物组成分，这在一项研究中也得到了证实 黑色素瘤模型。我们假设应答微生物群落促进了一种高度的 抗肿瘤炎症的基线水平，有助于刺激免疫治疗对GBM的疗效。 使用我们的新型人源化微生物组小鼠模型，这项提议试图揭示人类微生物- 包括T细胞在内的GBM临床前模型对免疫治疗反应的免疫机制(AIM 1)和(目标2)介导的作用，并评估应答者微生物群是否可以开发和利用 从治疗上讲。总体而言，我们试图加强我们对人类微生物区系在先天和 适应性免疫-微生物相互作用，并展示应答“最佳”的翻译潜力 微生物群。

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.