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.

项目总结/摘要 患有胰腺导管腺癌（PDAC）并且没有临床可检测到的转移的患者通过以下治疗： 手术然而，>70%的此类患者后来发生转移，最常见于肝脏。这有力 证据表明，转移可能起源于播散性癌细胞（DCC）。虽然大多数DCC被淘汰， 在免疫系统的作用下，一些DCC通过经历G 0/G1细胞周期停滞而逃避免疫监视。等 非增殖性DCC可随后增殖并形成致死性转移。是什么驱使休眠的DCC繁殖- 对恶性肿瘤的发生、逃避免疫监视和转移的机制知之甚少，这主要是由于缺乏 合适的模型。在这里，我们建立了一种新的PDAC小鼠模型的休眠DCC在肝脏中，使用 免疫方案后，脾内注射PDAC细胞，我们发现大多数DCC是埃利姆- 在这种“免疫”小鼠中，有一些作为单一的非增殖性DDC存活下来，并保持休眠状态， 个月在F99阶段，我们将使用这种休眠的PDAC小鼠模型来研究什么可以驱动DCC 以及免疫细胞如何调节转移。PDAC患者的糖皮质激素含量高出2倍 (GCs)，一种免疫调节应激激素。模仿这种临床现象，我们 用GC处理DCC宿主小鼠，使小鼠的GC增加2倍，我们发现DCC开始 增殖。此外，肿瘤微环境（TME）在GC治疗后发生变化：中性粒细胞的数量 增加，而T细胞和自然杀伤（NK）细胞减少。GCs治疗不引起转移，T 细胞耗竭仅在一小部分小鼠中引起少量转移。然而，当GCs治疗 结合T细胞耗竭，在所有检查的小鼠中观察到多个转移。根据提议，我们将 定义和靶向触发DCC增殖的信号，阐明GC对T细胞的作用机制， NK细胞抑制。在K 00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。晚期衰老是癌症的最重要的风险因素， 特定的转移性癌症类型，包括PDAC。衰老会显著改变TME，包括免疫细胞 分布和效应子功能、成纤维细胞活性、ECM和分泌因子。然而，这些 与DCC的转移复发相关的变化是未知的。我的博士后研究兴趣是 研究衰老诱导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， 以及它们对休眠DCC的顺序影响。最终，我打算成为一名独立调查员， 领导研究团队研究癌症休眠和TME，并产生知识以促进 靶向治疗，防止转移和提高生存率。