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

项目摘要 肠道微生物组的组成已被证明可以决定对抗生素的反应性或抗性。 免疫检查点抑制剂（ICI），如抗PD-1，用于黑色素瘤和其他癌症患者。不幸的是， 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，但该疗法并不 在人类中表现出功效。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之间存在显着差异 组合物的为了解决这一异常，我们开发了一种新的人源化微生物组（HuM）模型来研究微生物组中的微生物。 在GBM的临床前小鼠模型中对免疫疗法的应答。我们最近发表了各种各样的 人类微生物组组成可以决定T细胞ICI（抗PD-1）在临床前GBM中的功效 模型我们是第一个报道人类微生物群影响GBM小鼠模型中T细胞ICI反应的人， 这表明对于GBM患者，可能存在有益的微生物，可以增加ICI的疗效。 此外，GBM中最大部分的免疫细胞是肿瘤相关的巨噬细胞和小胶质细胞 （TAM）。到目前为止，还没有研究检查微生物组在响应TAM靶向治疗中的作用， 如CSF 1 R抑制或抗CD 47。此外，问题仍然是，“响应”是否 可以在治疗上利用微生物群落来挽救对治疗的抗性，或者如果“抗性” 微生物群落可以被耗尽和/或替换。 我们已经鉴定了“应答者”或最佳人类微生物组组成，以及“非应答者”或最佳人类微生物组组成。 我们的临床前GBM模型中的耐药人类微生物组组成，这也已在一项研究中得到证实。 黑素瘤模型。我们假设响应微生物群落促进了 抗肿瘤炎症的基线水平，这有助于刺激免疫疗法在GBM中的功效。 使用我们新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临床前模型中对免疫疗法应答的免疫机制，包括T细胞（Aim 1)和TAM（目标2）介导的作用，并评估是否可以开发和使用响应微生物组 治疗上总的来说，我们寻求提高我们对人类微生物群在先天性和 适应性免疫-微生物相互作用，并证明应答者“最佳”的翻译潜力 微生物群落

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.