Role of NK cells in control of HCV infection associated hepatocellular carcinoma

NK 细胞在控制 HCV 感染相关肝细胞癌中的作用

• 批准号: 10412907
• 负责人: Donald D Anthony
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412907
• 关键词: Age; Aging; Biological Assay; Biological Markers; Blood; Cause of Death; Cellular Assay; Chronic Hepatitis; Chronic Hepatitis C; Cirrhosis; Clinical Trials; Clinical Trials Design; Cryopreservation; Cytolysis; Data; Diagnosis; Doctor of Philosophy; Elderly; Epidemic; Funding; Genes; Granzyme; Hepatitis C; Hepatitis C Therapy; Hepatitis C virus; Host Defense; Immune response; Immunity; In Vitro; Incidence; Individual; Infection; Interferon Type II; Interferon-alpha; Interferons; Investigation; Liver; Liver diseases; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metastatic to; Monitor; Morbidity - disease rate; NK Cell Activation; NK cell therapy; Natural Killer Cells; Onset of illness; Outcome; PD-1 blockade; PD-1 pathway; Participant; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Play; Population; Prevention strategy; Primary carcinoma of the liver cells; Recording of previous events; Regimen; Regulatory Pathway; Risk; Role; Running; Signal Transduction; T-Lymphocyte; TNF gene; Therapeutic; Time; United States; Untranslated RNA; Veterans; Work; anti-cancer; cancer therapy; case control; design; diagnostic strategy; disorder risk; end stage liver disease; hepatocellular carcinoma cell line; high risk; immune function; improved; in vivo; knock-down; liver transplantation; metastatic colorectal; military veteran; mortality; novel diagnostics; patient population; predictive marker; programmed cell death protein 1; response; screening; targeted treatment; transcriptomics; treatment strategy; tumor

Remarkable advances with hepatitis C Virus (HCV) infection therapy have been made over the past 5 years,. At the same time, the peak of morbidity for the HCV epidemic, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC) will not occur until 2030. In fact, HCC is one of the fastest growing cancer related causes of death in the US. Certainly, at some point successful therapy for HCV will reduce the incidence of HCC. Though when this will be realized is unclear, in part due to the fact that the chronic HCV- infected patient population is aging, and older age HCV-infected patients do not appear to derive the same reduction in morbidity after successful HCV therapy as do their younger counterparts. At present, our local VA station (Station 541, Cleveland) follows 3,428 HCV patients, and over the past 3 years has treated over 1,500 of these with IFN-free therapy. Still, we accrue 25-43 new HCC cases/year, running at a steady rate over the past 6 years. Better strategies to more precisely identify those at high risk for HCC, and treat early HCC are much needed to curb this morbidity/mortality. PD1 blockade is an emerging therapy, and while a role for T cells in mediating effects of PD1 blockade have been defined, a role for NK cell activity is less defined. At the same time NK cells are a dominant lymphocyte population within the liver, NK cells are known to contribute to control of HCV infection itself, and NK cells have anti-cancer effector function. We will follow our well characterized HCV infected patient population, taking an NK cell, pathway focused approach to evaluate the anti-tumor host immune response that precedes HCV associated HCC diagnosis, to help identify both predictive markers and new treatment strategies. We hypothesize that NK cells play an integral role in host defense against HCV associated HCC, that selective enhancement of NK cell immune function through modulation of the IFN response or PD1 signaling can be harnessed to improve host anti-HCC immunity with therapeutic potential. Defining NK cell immunity that precedes HCC diagnosis will inform when and how to best inform PD1 or NK targeted clinical trial design, and potentially provide biomarkers of disease risk or onset. We will investigate this hypothesis with the following aims: Aim 1: Determine the role of PD1 on NK cell expansion and anti-HCC activity. Aim 2: Determine the effect of selective targeting the Long Non-Coding RNA (lncRNA) NRIR (negative regulator of interferon response) in enhancing IFN-dependent anti-HCC activity. Aim 3: Define NK cell activation state, function, PD1 pathway engagement and IFN regulatory pathway engagement prior to diagnosis of HCC.

在过去的5年中，丙型肝炎病毒（HCV）感染疗法取得了显着进步。 同时，HCV流行病的发病率峰，包括肝硬化和 肝细胞癌（HCC）直到2030年才会发生。实际上，HCC是生长最快的癌症之一 美国的死亡原因。当然，在某个时候，HCV成功疗法将减少 HCC的发病率。尽管当这将实现时尚不清楚，但部分原因是慢性HCV- 受感染的患者人群正在衰老，年龄较大的HCV感染患者似乎并未得出相同 成功的HCV治疗后，发病率降低，年轻的疗法也是如此。目前，我们当地的弗吉尼亚州 车站（第541号，克利夫兰）遵循3,428例HCV患者，在过去的3年中，已经治疗了1,500多个 其中包括无IFN疗法。尽管如此，我们还是每年累积25-43例新的HCC病例，以稳定的速度运行 过去6年。更好的策略更精确地识别出HCC高风险和治疗早期HCC的策略是 遏制这种发病率/死亡率非常需要。 PD1封锁是一种新兴疗法，而T细胞的作用 在定义了PD1阻滞的介导作用中，NK细胞活性的作用较少。同样 时间NK细胞是肝内主要淋巴细胞群，NK细胞已知有助于对照 HCV感染本身，NK细胞具有抗癌效应子功能。我们将遵循我们的特征 HCV感染的患者人群，采用NK细胞，集中途径的方法来评估抗肿瘤宿主 在HCV相关的HCC诊断之前的免疫反应，以帮助识别预测标记和 新的治疗策略。我们假设NK细胞在宿主防御HCV中起着不可或缺的作用 相关的HCC，通过调制IFN的选择性增强NK细胞免疫功能 可以利用反应或PD1信号传导，以改善具有治疗潜力的宿主抗HCC免疫。 定义在HCC诊断之前定义NK细胞免疫力将告知何时以及如何最佳告知PD1或NK 有针对性的临床试验设计，并有可能提供疾病风险或发作的生物标志物。我们将调查此事 以下目标假设：目标1：确定PD1在NK细胞扩张和抗HCC中的作用 活动。 AIM 2：确定靶向长的非编码RNA（LNCRNA）NRIR的效果 （干扰素反应的负调节剂）在增强IFN依赖性抗HCC活性方面。目标3： 定义NK细胞激活状态，功能，PD1途径参与和IFN调节途径 诊断HCC之前的参与度。