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

在过去的5年中，丙型肝炎病毒（HCV）感染治疗取得了显着进展。 与此同时，HCV流行的发病率高峰，包括肝硬化和 肝细胞癌（HCC）在2030年之前不会发生。事实上，HCC是增长最快的癌症之一， 在美国的死亡原因。当然，在某种程度上，成功的HCV治疗将减少 HCC的发病率。虽然这一点何时实现尚不清楚，部分原因是慢性HCV- 感染的患者人群正在老龄化，老年HCV感染患者似乎并不相同 在成功的HCV治疗后，他们的年轻同行的发病率降低。目前，我们当地的VA 克利夫兰541站跟踪了3,428名HCV患者，在过去3年中治疗了1500多名患者 这些患者的IFN治疗。尽管如此，我们每年仍有25-43例新的HCC病例，在2010年以稳定的速度运行。 过去6年。更好的策略，以更准确地识别那些在肝癌的高风险，并治疗早期肝癌是 这是遏制这一发病率/死亡率的迫切需要。PD 1阻断是一种新兴的治疗方法，虽然T细胞的作用 虽然已经确定了在介导PD 1阻断作用中的作用，但NK细胞活性的作用较少确定。在同一 当NK细胞是肝脏内的主要淋巴细胞群时，已知NK细胞有助于控制 HCV感染本身，NK细胞具有抗癌效应功能。我们将遵循我们的良好特点， HCV感染患者人群，采取NK细胞、通路聚焦的方法评价抗肿瘤宿主 在HCV相关HCC诊断之前的免疫应答，以帮助识别预测标志物和 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，即通过调节IFN选择性增强NK细胞免疫功能 因此，可以利用免疫应答或PD 1信号传导来改善具有治疗潜力的宿主抗HCC免疫力。 在HCC诊断之前定义NK细胞免疫将告知何时以及如何最好地告知PD 1或NK 有针对性的临床试验设计，并可能提供疾病风险或发病的生物标志物。我们会调查的 目的1：确定PD 1在NK细胞扩增和抗HCC中的作用 活动目的2：确定选择性靶向长非编码RNA（lncRNA）NRIR的效果 （干扰素应答的负调节因子）在增强IFN依赖性抗HCC活性中的作用。目标3： 定义NK细胞活化状态、功能、PD 1通路参与和IFN调节通路 在诊断出HCC之前，

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.