Immune Regulation of Dormancy at the Metastatic Site

转移部位休眠的免疫调节

• 批准号: 10744395
• 负责人: Xiao Han
• 金额: $ 4.92万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744395
• 关键词: Address; Adjuvant; Adjuvant Therapy; Adult; Age; Aging; Anxiety; Behavior; Binding; CDK4 gene; Cause of Death; Cell Communication; Cell Cycle Arrest; Cell Cycle Progression; Cell Proliferation; Cells; Chromatin; Clinical; Data; Development; Disease-Free Survival; Disseminated Malignant Neoplasm; Distant; Elderly; Enzymes; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Frequencies; Glucocorticoid Receptor; Glucocorticoids; Goals; Growth; Hormones; Image; Immune; Immune response; Immune system; Immunization; Immunize; Immunohistochemistry; Immunologic Surveillance; In Vitro; Injections; Internet; Knowledge; Lead; Literature; Liver; Liver neoplasms; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Modeling; Mus; Natural Killer Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Patients; Phase; Postdoctoral Fellow; Primary Neoplasm; Proliferating; Protocols documentation; Relapse; Research; Research Personnel; Resected; Risk Factors; Role; Signal Induction; Signal Transduction; Site; Source; Stimulus; Stress; Stromal Cells; T-Cell Depletion; T-Lymphocyte; Therapeutic; Tissues; aged; cancer cell; cancer therapy; cancer type; clinically relevant; experience; extracellular; immune clearance; immunoregulation; improved; interest; mouse model; neutrophil; novel; pancreatic ductal adenocarcinoma cell; prevent; targeted treatment; therapy design; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Patients with pancreatic ductal adenocarcinoma (PDAC) and no clinically detectable metastases are treated by surgery. However, >70% of such patients later develop metastases, most frequently in the liver. This is strong evidence that metastases can originate from disseminated cancer cells (DCCs). While most DCCs are eliminated by the immune system, a few DCCs escape immune surveillance by undergoing G0/G1 cell cycle arrest. Such non-proliferating DCCs can later proliferate and form lethal metastasis. What drives the dormant DCCs to prolif- erate, escape immune surveillance, and establish metastases are poorly understood, largely due to a lack of appropriate models. Here, we have established a novel PDAC mouse model of dormant DCCs in the liver, using an immunization protocol followed by intrasplenic injection of PDAC cells, we found that most DCCs were elim- inated in such “immunized” mice, but a few survived as single, non-proliferating DDCs and stayed dormant for months. In the F99 phase, we will use this dormant PDAC mouse model to examine what could drive DCC proliferation and how immune cells regulate metastasis. Patients with PDAC have 2-fold higher glucocorticoids (GCs), an immunomodulatory stress hormone, than healthy adults. Mimicking this clinical phenomenon, we treated DCC-hosting mice with GCs, achieving a 2-fold increase of GC in mice, we found that DCCs began to proliferate. In addition, the tumor microenvironment (TME) changed upon GCs treatment: numbers of neutrophils increased while T cells and natural killer (NK) cells decreased. GCs treatment did not cause metastasis, and T cell depletion caused only a few metastases in a small fraction of mice. However, when GCs treatment was combined with T cell depletion, multiple metastases were observed in all mice examined. As proposed, we will define and target the signals that trigger DCC proliferation and elucidate the mechanisms of GCs on T cells and NK cells suppression. In the K00 phase, I plan to investigate immune-fibroblast crosstalk that regulate cancer dormancy in the context of aging. Advanced aging is the most important risk factor for cancer overall and for specific metastatic cancer types including PDAC. Aging changes the TME significantly, including immune cells distributions and effector functions, fibroblasts activities, ECM, and secreted factors. However, how these changes are relevant to the metastasis relapse from DCCs is unknown. My postdoctoral research interest is to study aging-induced changes in immune cells and fibroblasts, with a focus on the immune-fibroblast crosstalk, and their sequential influences on dormant DCCs. Eventually, I plan to become an independent investigator, lead a research team to study cancer dormancy and TME, and generate knowledge to facilitate development of target therapies that prevent metastasis and improve survival.

项目摘要/摘要 胰腺导管腺癌（PDAC）的患者没有临床检测到的转移。 外科手术。但是，> 70％的此类患者后来发展转移，最常见于肝脏。这很强大 传播癌细胞（DCC）可以起源于转移的证据。而大多数DCC被淘汰 通过免疫系统，通过进行G0/G1细胞周期停滞，一些DCC避免了免疫监视。这样的 非增殖的DCC可以随后增殖并形成致命的转移。是什么驱动休眠DCC到Prolife- 食用，逃避免疫保护监测和建立转移量的理解很少，这在很大程度上是由于缺乏 适当的模型。在这里，我们使用了一种新型的PDAC小鼠在肝脏中休眠DCC的PDAC小鼠模型，并使用 免疫方案，然后是全民内注射PDAC细胞，我们发现大多数DCC是消除的 在这种“免疫”小鼠中含有诱因，但其中一些人作为单一的，非增殖的DDC幸存下来，并保持了休眠状态 月份。在F99阶段，我们将使用此休眠PDAC鼠标模型来检查什么可能驱动DCC 增殖以及免疫细胞如何调节转移。 PDAC患者的糖皮质激素高2倍 （GCS），一种免疫调节胁迫，比健康的成年人。模仿这种临床现象，我们 用GC治疗的DCC托管小鼠，在小鼠的GC中增加了2倍，我们发现DCC开始开始 增生。此外，GCS治疗后肿瘤微环境（TME）发生了变化：中性粒细胞数量 T细胞和天然杀手（NK）细胞的增加，减少了。 GCS治疗不会引起转移，t 细胞耗竭仅在一小部分小鼠中引起几个转移。但是，当GCS治疗是 结合T细胞耗竭，在所有检查的小鼠中都观察到了多种转移。根据提议，我们将 定义并定义触发DCC增殖的信号并阐明T细胞上GC的机制 NK细胞抑制。在K00阶段，我计划研究调节癌症的免疫成纤维细胞串扰 在衰老的背景下休眠。高级衰老是总体癌症和癌症最重要的危险因素 包括PDAC在内的特定转移性癌症类型。衰老会显着改变TME，包括免疫细胞 分布和效应子功能，成纤维细胞活动，ECM和分泌因素。但是，这些是如何的 变化与DCC的转移中继有关。我的博士后研究兴趣是 研究衰老引起的免疫细胞和成纤维细胞的变化，重点是免疫成纤维细胞串扰， 它们对休眠DCC的顺序影响。最终，我计划成为一名独立调查员， 领导研究小组研究癌症休眠和TME，并产生知识以促进发展 靶疗法可防止转移并改善生存率。