Microenvironment and Arsenic Lung Tumorigenesis

微环境与砷肺肿瘤发生

• 批准号: 9766291
• 负责人: Gang Chen
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766291
• 关键词: A/J Mouse; Animal Model; Animals; Antibodies; Arsenic; Binding; CD4 Positive T Lymphocytes; CD4/CD8 ratio procedure; CD8B1 gene; Cancer Patient; Cell Count; Cell membrane; Cells; Cellular Structures; Chronic; Data; Development; Dose; Environmental Exposure; Environmental Risk Factor; Epithelial Cells; Equilibrium; Flow Cytometry; Functional disorder; Genes; Human; Immune; Immune system; Immunity; Immunologic Monitoring; Immunologic Surveillance; In Vitro; Incidence; Injections; Interleukin-6; Investigation; Knock-out; Lead; Lung; Lung Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Mediating; Modeling; Monitor; Mus; Outcome; PD-1/PD-L1; PDCD1LG1 gene; Pathway interactions; Pharmacologic Substance; Play; Process; Receptor Inhibition; Regulation; Reporting; Role; SLEB2 gene; STAT3 gene; Skin Cancer; T-Lymphocyte; T-Lymphocyte Subsets; Tumor Escape; Tumor Immunity; Up-Regulation; cell transformation; cell type; cytotoxic; effector T cell; genetic approach; immune activation; immune checkpoint; in vivo; inhibiting antibody; inhibitor/antagonist; innovation; lung carcinogenesis; lung tumorigenesis; mouse model; neoplastic cell; novel; novel strategies; prevent; promoter; tumor; tumor initiation; tumorigenesis

Abstract Chronic exposure of environmental arsenic promotes skin, bladder, liver and lung cancers. However, the mechanism underlying arsenic lung carcinogenesis is unclear. Evidence from animal models and studies in cancer patients indicate that the immune system monitors the host body recognizing and reacting against newly arising transformed/tumor cells to stop/control tumor formation. The encounter between the immune system and transformed/tumor cells initiates a process termed “immunoediting” that can bring about three outcomes: elimination, equilibrium or escape of transformed/tumor cells from immune control. Host immunity suppresses tumor development, whereas tumor formation implies the successful escape of transformed/tumor cells from the surveillance of the immune system. Effector T cells, particularly cytotoxic T (Tc) cells, represent a major component of cell-mediated anti-tumor immunity. One of the mechanisms modulating T cell antitumor effector function involves the activation/inhibition receptors on a T cell membrane. Inhibition of T cell antitumor function through the activation of immune checkpoint pathways (e.g. PD-1/PD-L1 pathway) has been shown to promote tumor cell immune escape and tumor formation. In addition, previous reports indicate that the aberrant activation of STAT3 occurs in many human tumors and STAT3-mediated PD-L1 up-regulation impedes T cell antitumor function. Our previous in vitro study showed that the IL-6/STAT3 axis plays a critical role in arsenic- induced transformation in human bronchial epithelial cells. Using a lung tumor mouse model, our new preliminary data show that long-term arsenic exposure increased lung tumor incidence rate and multiplicity of A/J mice. In addition, arsenic exposure dose-dependently activated STAT3, increased the binding of STAT3 to the promoter of the PD-L1 gene and up-regulated PD-L1 in mouse lungs. Flow cytometry data further indicated that arsenic increased PD-1+ T cell numbers and decreased CD8+/CD4+ T cell ratio in the lungs, while injection of PD-1 or PD-L1 antibodies reversed the decreased CD8+/CD4+ ratio. Since PD-1/PD-L1 up-regulation may inhibit T cell antitumor function and promote escape of transformed cells from host immunosurveillance and eventually lead to tumor formation, we hypothesize that arsenic promotes lung tumor formation through STAT3/PD-1/PD-L1-mediated inhibition of T cell antitumor function. Three specific aims are proposed: Aim 1: To determine if chronic arsenic exposure inhibits T cell antitumor function and the types of cells in which PD-1 or PD-L1 is up-regulated by arsenic in the lungs of A/J mice. Aim 2: To determine if inhibition of the PD-1/PD-L1 pathway ameliorates arsenic-promoted T cell dysfunction and tumor formation in the lungs of A/J mice. Aim 3: To determine if activation of STAT3 is the mechanism underlying arsenic-enhanced PD-L1 up- regulation, T cell dysfunction and tumor formation in the lungs of A/J mice.

抽象的 长期接触环境砷会促进皮肤癌、膀胱癌、肝癌和肺癌。然而， 砷引起肺癌的机制尚不清楚。来自动物模型和研究的证据 癌症患者表示，免疫系统会监控宿主身体的识别和反应 新产生的转化/肿瘤细胞以阻止/控制肿瘤形成。免疫之间的相遇 系统和转化/肿瘤细胞启动一个称为“免疫编辑”的过程，可以带来三个 结果：转化细胞/肿瘤细胞的消除、平衡或逃脱免疫控制。宿主免疫 抑制肿瘤的发展，而肿瘤的形成意味着转化/肿瘤的成功逃脱 细胞免受免疫系统的监视。效应 T 细胞，特别是细胞毒性 T (Tc) 细胞，代表 细胞介导的抗肿瘤免疫的主要组成部分。调节T细胞抗肿瘤的机制之一 效应器功能涉及 T 细胞膜上的激活/抑制受体。抑制T细胞抗肿瘤 通过激活免疫检查点通路（例如 PD-1/PD-L1 通路）发挥作用已被证明 促进肿瘤细胞免疫逃逸和肿瘤形成。此外，之前的报道表明，异常情况 STAT3 的激活发生在许多人类肿瘤中，STAT3 介导的 PD-L1 上调会阻碍 T 细胞 抗肿瘤功能。我们之前的体外研究表明，IL-6/STAT3 轴在砷- 诱导人支气管上皮细胞转化。使用肺肿瘤小鼠模型，我们的新 初步数据表明，长期接触砷会增加肺部肿瘤的发病率和多重性 A/J 小鼠。此外，砷暴露剂量依赖性地激活 STAT3，增加了 STAT3 与 STAT3 的结合。 PD-L1 基因的启动子和小鼠肺中 PD-L1 的上调。流式细胞术数据进一步表明 砷增加了肺中 PD-1+ T 细胞数量并降低了 CD8+/CD4+ T 细胞比率，而注射 PD-1 或​​ PD-L1 抗体逆转了降低的 CD8+/CD4+ 比率。由于 PD-1/PD-L1 上调可能 抑制T细胞抗肿瘤功能并促进转化细胞逃避宿主免疫监视 最终导致肿瘤形成，我们假设砷通过以下途径促进肺肿瘤形成 STAT3/PD-1/PD-L1 介导的 T 细胞抗肿瘤功能抑制。提出了三个具体目标： 目标 1：确定慢性砷暴露是否会抑制 T 细胞抗肿瘤功能以及细胞类型 A/J 小鼠肺部的砷会上调 PD-1 或​​ PD-L1。 目标 2：确定抑制 PD-1/PD-L1 通路是否可以改善砷促进的 T 细胞功能障碍 以及 A/J 小鼠肺部肿瘤的形成。 目标 3：确定 STAT3 的激活是否是砷增强 PD-L1 上调的潜在机制 A/J 小鼠肺部的调节、T 细胞功能障碍和肿瘤形成。