Pglyrp3 cooperates with Snail1 to mediate anti-tumor immune response in breast cancer

Pglyrp3与Snail1合作介导乳腺癌的抗肿瘤免疫反应

基本信息

  • 批准号:
    10215253
  • 负责人:
  • 金额:
    $ 4.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-16 至 2022-05-15
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract This application seeks to understand the mechanism of breast cancer’s relative resistance to immunotherapy, including immune checkpoint inhibitors, and to identify potential targets to overcome this resistance. Immune escape is a hallmark of disease progression and metastasis and a major impediment to designing efficacious anticancer therapies. Breast cancer is considered less immunogenic, and thus relatively resistant to immunotherapy such as immune checkpoint inhibitors (ICI), although there is evidence of only a modest response to ICIs in patients with triple negative breast cancer (TNBC) compared to other breast cancer subtypes. The exact mechanism for this relative resistance of breast cancer to ICIs remains unclear. However it is increasingly clear that recruiting inhibitory immune cells such as regulatory T cells (Treg) to the tumor microenvironment is an effective way tumors employ to suppress effective anti-tumor immunity and promote immune escape. In this proposal, we describe the application of a novel computational approach to identify and validate the underlying tumor cell-intrinsic molecular determinants of intratumoral Treg stability and immune escape. Our objective is to identify novel targets in breast cancer to prevent immune escape and to enhance breast cancer’s response to ICIs. To that end we have discovered a novel subnetwork regulated by Snail1, a master epithelial-to-mesenchymal transition (EMT) initiating factor, which is predicted to confer an immune surveillance program by suppressing the intratumoral Treg population. The central hypothesis of this proposal is that Snail1 negatively regulates Pglyrp3, a protein known for its Treg recruitment functions, therefore limiting the Treg population, enhancing anti-tumor immunity and response to ICIs. In Aim 1, we will determine the impact of the Snail1-Pglyrp3 interaction on intratumoral Treg stability using breast cancer models. Specifically, we will manipulate levels of Pglyrp3 in Snail1-positive or -negative backgrounds and determine how the intratumoral Treg population is impacted and whether additional factors are required for the Snail1-Pglyrp3 interaction to be functional. In Aim 2, we will determine whether targeting the Snail1-Pglyrp3 interaction is sufficient at enhancing response to immune checkpoint inhibitors and improving survival. This work is significant because it will demonstrate a novel network involved in switching from an immune-active to immune-suppressed tumor microenvironment that shapes tumor evolution. This work is innovative in that it will provide novel targets that can be pursued to prevent breast tumors from immune evasion and to sensitize them to ICIs.
项目摘要/摘要 该应用程序旨在了解乳腺癌对免疫疗法相对抵抗的机制, 包括免疫检查点抑制剂,并确定潜在的靶标以克服这种抗性。免疫 逃生是疾病进展和转移的标志,也是设计高效的主要障碍 抗药疗法。乳腺癌被认为不那么免疫原性,因此对 免疫疗法,例如免疫粘液抑制剂(ICI),尽管只有适度的证据 与其他乳腺癌亚型相比,三重阴性乳腺癌(TNBC)患者对ICI的反应。 乳腺癌对ICIS的相对耐药性的确切机制尚不清楚。但是是 越来越清楚地表明,募集抑制性免疫细胞,例如调节T细胞(Treg)到肿瘤 微环境是抑制有效的抗肿瘤免疫并促进有效的肿瘤员工的有效方法 免疫逃脱。在此提案中,我们描述了一种新型计算方法来识别和 验证肿瘤内Treg稳定性和免疫的潜在肿瘤细胞中性分子确定剂 逃脱。我们的目标是确定乳腺癌的新靶标,以防止免疫逃脱并增强。 乳腺癌对ICIS的反应。为此,我们发现了一个由Snail1调节的新颖子网,一个 主上皮到间质转变(EMT)发起的因子,预计将赋予免疫 通过抑制肿瘤内Treg人群来监视计划。该提议的核心假设是 Snail1负调节PGLYRP3,PGLYRP3是一种以TREG募集功能而闻名的蛋白质,因此限制了 Treg人群,增强了抗肿瘤免疫力和对ICIS的反应。在AIM 1中,我们将确定 使用乳腺癌模型在肿瘤内Treg稳定性上的Snail1-PGlyrp3相互作用。具体来说,我们会的 在蜗牛阳性或负背景中操纵pGlyrp3级别,并确定肿瘤内的方式 Treg人口受到影响,以及是否需要其他因素才需要蜗牛1-pglyrp3相互作用 功能。在AIM 2中,我们将确定针对Snail1-Pglyrp3相互作用是否足以增强 对免疫检查点抑制剂的反应并改善生存率。这项工作很重要,因为它将 展示一个新的网络,涉及从免疫活性转变为免疫抑制的肿瘤 微环境塑造肿瘤的演变。这项工作具有创新性,因为它将提供新颖的目标 可以追求以防止乳腺肿瘤免疫避免,并将其感知到ICIS。

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

Mathew Sebastian的其他基金

Pglyrp3 cooperates with Snail1 to mediate anti-tumor immune response in breast cancer
Pglyrp3与Snail1合作介导乳腺癌的抗肿瘤免疫反应
  • 批准号:
    9763323
    9763323
  • 财政年份:
    2018
  • 资助金额:
    $ 4.71万
    $ 4.71万
  • 项目类别:

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Pglyrp3 cooperates with Snail1 to mediate anti-tumor immune response in breast cancer
Pglyrp3与Snail1合作介导乳腺癌的抗肿瘤免疫反应
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