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.

项目概要/摘要 患有胰腺导管腺癌 (PDAC) 且临床上未检测到转移的患者接受以下治疗： 然而，>70% 的此类患者随后会出现转移，最常见的是肝脏转移。 有证据表明转移可能源自播散性癌细胞 (DCC)，而大多数 DCC 已被消除。 在免疫系统的作用下，一些 DCC 通过经历 G0/G1 细胞周期停滞来逃避免疫监视。 不增殖的 DCC 随后会增殖并形成致命的转移，是什么驱使休眠的 DCC 增殖。 人们对如何加速、逃避免疫监视和建立转移知之甚少，这主要是由于缺乏 在这里，我们使用肝脏中休眠的 DCC 建立了一种新型 PDAC 小鼠模型。 免疫方案随后脾内注射 PDAC 细胞，我们发现大多数 DCC 都被消除了 在这种“免疫”的小鼠体内，但有一些以单一的、不增殖的 DDC 形式存活下来，并保持休眠状态 在 F99 阶段，我们将使用这个休眠的 PDAC 小鼠模型来研究什么可以驱动 DCC。 增殖以及免疫细胞如何调节转移。 PDAC 患者的糖皮质激素水平高出 2 倍。 （GC），一种免疫调节应激激素，比健康成年人模仿这种临床现象，我们。 携带 GC 的 DCC 小鼠，小鼠的 GC 增加了 2 倍，我们发现经过处理的 DCC 开始 此外，GC 治疗后肿瘤微环境 (TME) 发生变化：中性粒细胞数量。 GCs 治疗不会引起转移，而 T 细胞和自然杀伤 (NK) 细胞减少。 然而，当 GC 治疗时，细胞耗竭仅在一小部分小鼠中引起少量转移。 结合 T 细胞耗竭，在所有检查的小鼠中均观察到多处转移。 定义和靶向触发 DCC 增殖的信号，并阐明 GC 对 T 细胞和 在 K00 阶段，我计划研究调节癌症的免疫成纤维细胞串扰。 衰老背景下的休眠是整​​体癌症和癌症最重要的危险因素。 特定的转移性癌症类型（包括 PDAC）会显着改变 TME，包括免疫细胞。 分布和效应器功能、成纤维细胞活性、ECM 和分泌因子然而，这些如何。 与 DCC 转移复发相关的变化尚不清楚。 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的串扰， 最终，我计划成为一名独立调查员， 领导一个研究团队研究癌症休眠和 TME，并产生知识以促进癌症的发展 预防转移和提高生存率的靶向治疗。