(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: 9335107
• 负责人: BRINDA EMU
• 金额: $ 71.9万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335107
• 关键词: Address; Affect; 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 and Related Disorders; Immune response; Immune system; Immunologic Deficiency Syndromes; Immunologics; Immunosuppressive Agents; Immunotherapy; Impairment; Incidence; Individual; Infection; 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; 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; antiretroviral therapy; base; cancer diagnosis; cancer prevention; cancer therapy; 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.

艾滋病毒感染患者有较高的发病率，许多癌症，往往与较差的预后， 有效的抗逆转录病毒治疗和癌症靶向治疗。鉴于T细胞耗竭已经被强烈地 与癌症的发病率和结果有关，了解慢性、持续性 炎症和T细胞功能障碍在发展成癌症的HIV患者中至关重要。我们的初步 鼠数据显示，暴露于脂肪酸促进T细胞耗竭的性质（例如增加的T细胞耗竭）。 PD-1表达和效应子功能的抑制）。我们还发现，游离脂肪酸（FFA）水平是 与健康对照组相比，在慢性病毒感染和黑色素瘤的小鼠模型中， 其中存在功能耗尽的PD-1hi T细胞。根据这些数据和初步数据 在HIV感染者中，我们认为脂质失调的存在和持续导致了 积极的促炎环境，直接导致T细胞功能障碍和PD-1增加 表情由于病毒感染和感染，艾滋病毒感染者中代谢综合征的发病率很高 抗逆转录病毒疗法本身进一步导致炎症和T细胞功能障碍。因此，我们将探索 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细胞的存在是否导致该群体中癌症发病率的增加。通过 利用一个完善的纵向队列，我们处于一个独特的位置，以解决免疫的作用， 功能障碍和脂质代谢对HIV感染者癌症发病率增加的影响。在 此外，我们将使用HIV感染的受试者样本和慢性病毒感染的小鼠模型， 确定升高的循环FFA和脂肪酸摄取对T细胞耗竭的影响。我们的目标是（1） 在HIV感染者中建立脂质失调和T细胞耗竭之间的联系， （2）在发展癌症的感染个体中，以及在来自HIV感染个体的肿瘤组织中; 游离脂肪酸（FFA）摄取通过转运蛋白如CD 36影响T细胞功能障碍的机制， 慢性感染的小鼠模型、癌症的小鼠模型和HIV感染个体;理解 代谢综合征和免疫抑制肿瘤环境之间炎症联系是重要的 发现预防和/或治疗癌症的新靶点，其中可能包括针对脂肪酸的干预措施， 发信号。