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
基本信息
- 批准号:10665439
- 负责人:
- 金额:$ 32.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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.
项目摘要
肠道微生物组的组成已被证明可以确定反应能力或抗性
黑色素瘤和其他癌症患者的免疫检查点抑制剂(ICI),例如抗PD-1。很遗憾,
尽管免疫疗法在胶质母细胞瘤(GBM)临床前小鼠模型中效果很好,但该疗法尚未
在人类中表现出效率。大多数临床前癌症研究都是在使用的小鼠模型中进行的
小鼠肠道微生物组,但小鼠和人类微生物之间存在显着差异
组成。为了解决这一异常,我们开发了一种新型的人性化微生物组(HUM)模型来研究
在GBM的临床前小鼠模型中对免疫疗法的反应。我们最近发表了各种各样的
人类微生物组组成可以决定在临床前GBM中T细胞ICI(抗PD-1)的效率
模型。我们是第一个报告人类微生物群会影响GBM小鼠模型中T细胞ICI响应的人
表明对于患有GBM的患者,可能有有益的微生物可以提高ICIS的效率。
此外,GBM中最大的免疫细胞是肿瘤相关的巨噬细胞和小胶质细胞
(tams)。迄今为止,尚无研究检查微生物组对TAM靶向疗法的作用,
例如GBM中的CSF1R抑制或抗CD47。此外,仍然存在“响应式”的问题
可以热探索中的微生物群落以挽救对疗法的抗性,或者是否“抗性”
可以降级和/或更换的微生物群落。
我们已经确定了“响应者”或最佳人类微生物组组成,以及“无反应器”或
我们的临床前GBM模型中的抗性人类微生物组组成,也已在A中证实
黑色素瘤模型。我们假设响应者微生物组群落促进了增强
抗肿瘤注射的基线水平,有助于刺激GBM免疫疗法的效率。
使用我们新型的人源性微生物小鼠模型,该建议旨在发现人类微生物 -
GBM临床前模型中对免疫疗法反应的免疫力学,包括T细胞(AIM
1)和TAM(AIM 2)介导的效果,并评估是否可以探索和使用响应者微生物组
在治疗上。总体而言,我们试图增强对人类微生物在先天和
自适应免疫微生物相互作用,并证明响应者“最佳”的翻译潜力
微生物组。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
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