(PQ1) Lipid Metabolism, Inflammation, and T cell Dysfunction in HIV-associated Cancer

(PQ1) HIV 相关癌症中的脂质代谢、炎症和 T 细胞功能障碍

• 批准号: 9893990
• 负责人: BRINDA EMU
• 金额: $ 6.99万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893990
• 关键词: AIDS related cancer; Address; Affect; Antitumor Response; Biological; CD36 Antigens; CD36 gene; CD8-Positive T-Lymphocytes; Cancer Model; Cancer Patient; Cell physiology; Chronic; Clinical; Cytotoxic T-Lymphocytes; Data; Environment; Environmental Risk Factor; Event; Exposure to; Fat-Restricted Diet; Fatty Acids; Functional disorder; HIV; HIV Infections; Human; Immune System Diseases; Immune system; Immunologic Deficiency Syndromes; Immunologics; Immunosuppressive Agents; Immunotherapy; Impairment; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Link; Lipids; Longitudinal cohort; Lymphocytic choriomeningitis virus; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Mus; Nonesterified Fatty Acids; Nuclear Receptors; Nucleosides; Obesity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Property; Protease Inhibitor; Proteins; Reverse Transcriptase Inhibitors; Risk Factors; Role; SLEB2 gene; Sampling; Signal Transduction; Specimen; T cell response; T-Lymphocyte; Tissues; Tumor Immunity; Tumor Tissue; Tumor-Infiltrating Lymphocytes; Up-Regulation; Viral; Viral Cancer; Virus Diseases; Work; anti-tumor immune response; antiretroviral therapy; base; cancer diagnosis; cancer prevention; cancer therapy; chronic infection; exhaust; exhaustion; immune activation; inflammatory milieu; lipid metabolism; melanoma; metabolic rate; mouse model; outcome forecast; preference; prevent; receptor; response; targeted cancer therapy; targeted treatment; tumor; uptake

Patients with HIV infection have higher incidence of many cancers and often with a poorer prognosis, despite effective antiretroviral therapy and cancer-targeted therapy. Given that T cell exhaustion has been strongly implicated in cancer incidence and outcome, understanding the connection between chronic, persistent inflammation and T cell dysfunction is critical among patients with HIV who develop cancer. Our preliminary murine data shows that exposure to fatty acids promotes properties of T cell exhaustion (such as increased PD-1 expression and suppression of effector functions). We also find that free fatty acids (FFAs) levels are significantly higher in murine models of chronic viral infection and melanoma compared to healthy controls, two settings in which functionally exhausted PD-1hi T cells are present. Based on these data and preliminary data in HIV infected individuals, we propose that the presence and persistence of lipid dysregulation results in an aggressively pro-inflammatory environment that directly contributes T cell dysfunction and increased PD-1 expression. The high rate of metabolic syndrome among HIV-infected individuals, due to viral infection and antiretroviral therapy itself, further contributes to inflammation and T cell dysfunction. We will thus explore whether there is a direct correlation between lipid dysregulation and T cell exhaustion in HIV-infected patients and whether presence of exhausted T cells results in increased cancer incidence in this population. By utilizing a well-established longitudinal cohort, we are in a unique position to address the role of immune dysfunction and lipid metabolism upon increased cancer incidence among HIV-infected individuals. In addition, we will use both HIV-infected subject samples and a murine model of chronic viral infection to determine the impact of elevated circulating FFA and fatty acid uptake on T cell exhaustion. Our aims will (1) establish a link between lipid dysregulation and T cell exhaustion in HIV-infected individuals, among HIV- infected individuals who develop cancer, and in tumor tissue from HIV-infected individuals; (2) define the mechanism by which free fatty acid (FFA) uptake, via transporters such as CD36, impacts T cell dysfunction in a murine model of chronic infection, a murine model of cancer, and in HIV-infected individuals; Understanding the inflammatory link between metabolic syndromes and immunosuppressive tumor environment is important to discover new targets to prevent and/or treat cancer, which may include interventions targeting fatty acid signaling.

HIV 感染患者许多癌症的发病率较高，而且预后往往较差，尽管 有效的抗逆转录病毒治疗和癌症靶向治疗。鉴于 T 细胞耗竭已严重 与癌症的发病率和结果有关，了解慢性、持续性之间的联系 炎症和 T 细胞功能障碍对于罹患癌症的 HIV 患者至关重要。我们的初步 小鼠数据表明，接触脂肪酸会促进 T 细胞衰竭的特性（例如增加 PD-1 表达和效应功能抑制）。我们还发现游离脂肪酸 (FFA) 水平 与健康对照相比，慢性病毒感染和黑色素瘤的小鼠模型显着更高，两个 存在功能衰竭的 PD-1hi T 细胞的环境。根据这些数据和初步数据 在艾滋病毒感染者中，我们认为脂质失调的存在和持续会导致 积极的促炎环境直接导致 T 细胞功能障碍和 PD-1 增加 表达。由于病毒感染和艾滋病毒感染，艾滋病毒感染者中代谢综合征的发病率很高 抗逆转录病毒治疗本身进一步导致炎症和 T 细胞功能障碍。我们将由此探索 HIV 感染者的脂质失调与 T 细胞耗竭之间是否存在直接相关性 以及耗尽的 T 细胞的存在是否会导致该人群癌症发病率增加。经过 利用完善的纵向队列，我们​​处于独特的地位来解决免疫的作用 HIV感染者癌症发病率增加导致功能障碍和脂质代谢。在 此外，我们将使用感染艾滋病毒的受试者样本和慢性病毒感染的小鼠模型来 确定循环 FFA 和脂肪酸摄取升高对 T 细胞耗竭的影响。我们的目标是 (1) 在 HIV 感染者、HIV-感染者中建立脂质失调与 T 细胞耗竭之间的联系 罹患癌症的感染者以及艾滋病毒感染者的肿瘤组织； (2) 定义 通过 CD36 等转运蛋白摄取游离脂肪酸 (FFA) 影响 T 细胞功能障碍的机制 慢性感染小鼠模型、癌症小鼠模型以及艾滋病毒感染者；理解 代谢综合征和免疫抑制肿瘤环境之间的炎症联系很重要 发现预防和/或治疗癌症的新目标，其中可能包括针对脂肪酸的干预措施 发信号。