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 环境砷的长期暴露可促进皮肤，膀胱，肝和肺癌。然而， 砷肺癌发生的基础机制尚不清楚。动物模型和研究的证据 癌症患者表明，免疫系统可以监视宿主身体识别和反应 新出现的转化/肿瘤细胞停止/控制肿瘤形成。免疫之间的相遇 系统和转换/肿瘤细胞启动一个称为“免疫修剪”的过程，该过程可带来三个 结果：消除，平衡或逃避转化的/肿瘤细胞免疫控制。宿主免疫 抑制肿瘤发育，而肿瘤的形成意味着转化/肿瘤的成功逃脱 来自免疫系统监视的细胞。效应T细胞，尤其是细胞毒性T（TC）细胞，代表 细胞介导的抗肿瘤免疫的主要成分。调节T细胞抗肿瘤的机制之一 效应子功能涉及T细胞膜上的激活/抑制接收器。抑制T细胞抗杀菌剂 通过激活免疫座点途径（例如PD-1/PD-L1途径）的功能已显示为 促进肿瘤细胞免疫逃生和肿瘤形成。此外，以前的报告表明异常 STAT3的激活发生在许多人类肿瘤中，STAT3介导的PD-L1上调阻碍了T细胞 抗肿瘤功能。我们以前的体外研究表明，IL-6/STAT3轴在砷中起关键作用 诱导人支气管上皮细胞的转化。使用肺肿瘤鼠标模型，我们的新 初步数据表明，长期砷暴露增加了肺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的STAT3，增加了STAT3与 PD-L1基因的启动子和小鼠肺中的PD-L1上调。流式细胞仪数据进一步指示 砷增加了PD-1+ T细胞数量，并增加了肺中CD8+/CD4+ T细胞的比率 PD-1或PD-L1抗体的抗体逆转了降低的CD8+/CD4+比。由于PD-1/PD-L1上调可能 抑制T细胞抗肿瘤功能，并促进转化的细胞从宿主免疫监视和 最终导致肿瘤形成，我们假设砷通过 STAT3/PD-1/PD-L1介导的T细胞抗肿瘤功能的抑制。提出了三个具体目标： 目标1：确定慢性砷暴露是否抑制T细胞抗肿瘤功能和细胞类型 哪个PD-1或PD-L1在A/J小鼠的肺中被砷上调。 目标2：确定抑制PD-1/PD-L1途径是否可以改善砷促进的T细胞功能障碍 A/J小鼠的肺中的肿瘤形成。 目标3：确定STAT3的激活是否是砷增强的PD-L1 UP-的基础机制 A/J小鼠肺中的调节，T细胞功能障碍和肿瘤形成。