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
• 负责人: Mathew Sebastian
• 金额: $ 4.1万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2022-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763323
• 关键词: Address; Anti-Bacterial Agents; Autoimmunity; Breast; Breast Cancer Model; Breast cancer metastasis; CCL17 gene; CCL22 gene; Cancer Etiology; Cells; Cessation of life; Computer Analysis; Data; Data Set; Detection; Disease Progression; Epithelial; Evolution; Gene Expression Profiling; Genes; Genetic; Goals; Immune; Immune checkpoint inhibitor; Immune system; Immunity; Immunologic Surveillance; Immunosuppressive Agents; Immunotherapy; Individual; Interleukin-17; Intrinsic factor; Mammary Neoplasms; Mediating; Mesenchymal; Modeling; Molecular; Mus; Neoplasm Metastasis; Pathway interactions; Patients; Penetrance; Play; Population; Prevention; Proteins; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Research; Resistance; Role; Shapes; Surveillance Program; Therapeutic; Tumor Escape; Tumor Immunity; Tumor Initiators; Woman; Work; anti-PD1 antibodies; anti-PD1 therapy; anti-tumor immune response; base; cancer subtypes; cancer therapy; chemokine; cytokine; design; disorder risk; effector T cell; epithelial to mesenchymal transition; human model; immunogenic; immunoregulation; implantation; improved; innovation; knock-down; malignant breast neoplasm; mouse model; neoplastic cell; novel; peptidoglycan recognition protein; prevent; recruit; response; small hairpin RNA; synergism; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumorigenesis

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.

项目总结/摘要 本申请旨在了解乳腺癌对免疫疗法的相对抗性的机制， 包括免疫检查点抑制剂，并确定克服这种耐药性的潜在靶点。免疫 逃逸是疾病进展和转移的标志，也是设计有效治疗方案的主要障碍。 抗癌疗法。乳腺癌被认为是免疫原性较低的，因此相对耐药。 免疫治疗，如免疫检查点抑制剂（ICI），虽然有证据表明，只有适度的 与其他乳腺癌亚型相比，三阴性乳腺癌（TNBC）患者对ICI的反应。 乳腺癌对ICI的这种相对抗性的确切机制仍不清楚。然而 越来越清楚的是，招募抑制性免疫细胞如调节性T细胞（Treg）到肿瘤中， 微环境是肿瘤用来抑制有效的抗肿瘤免疫和促进肿瘤生长的有效途径。 免疫逃逸在这个建议中，我们描述了一种新的计算方法的应用，以确定和 验证肿瘤内Treg稳定性和免疫调节的潜在肿瘤细胞内在分子决定因素， 逃跑我们的目标是确定乳腺癌中的新靶点，以防止免疫逃逸并增强免疫应答。 乳腺癌对ICIs的反应为此，我们发现了一个由Snail 1调控的新的子网络， 主上皮间质转化（EMT）启动因子，预计可赋予免疫 通过抑制肿瘤内Treg群体来监测程序。这一提议的核心假设是 Snail 1负调节Pglyrp 3，一种以Treg募集功能而闻名的蛋白质，因此限制了 Treg群体，增强抗肿瘤免疫和对ICI的应答。在目标1中，我们将确定 使用乳腺癌模型的Snail 1-Pglyrp 3相互作用对肿瘤内Treg稳定性的影响。具体来说，我们将 操纵Snail 1阳性或阴性背景中的Pglyrp 3水平，并确定肿瘤内 Treg群体受到影响，以及Snail 1-Pglyrp 3相互作用是否需要其他因素， 不降低在目标2中，我们将确定靶向Snail 1-Pglyrp 3相互作用是否足以增强 对免疫检查点抑制剂的反应和提高生存率。这项工作很重要，因为它将 展示了一种涉及从免疫活性肿瘤切换到免疫抑制肿瘤的新型网络 影响肿瘤演变的微环境。这项工作是创新的，因为它将提供新的目标， 可用于预防乳腺肿瘤的免疫逃避并使其对ICI敏感。