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

丙型肝炎病毒(丙型肝炎病毒)感染治疗在过去的5年中取得了显著的进展。 与此同时，丙型肝炎病毒流行的发病率高峰，包括肝硬变和 肝细胞癌要到2030年才会发生。事实上，肝癌是增长最快的癌症之一。 在美国的相关死因。当然，在某种程度上，成功的丙型肝炎治疗将减少 肝癌的发病率。尽管这将在何时实现尚不清楚，部分原因是慢性丙型肝炎病毒- 感染患者人口正在老龄化，而年龄较大的丙型肝炎病毒感染患者似乎并不相同 成功的丙型肝炎治疗后发病率降低，年轻的同龄人也是如此。目前，我们当地的退伍军人管理局 该站(克利夫兰541站)跟踪了3428名丙型肝炎患者，在过去3年中治疗了1500多名患者 其中接受不含干扰素治疗的患者。尽管如此，我们每年增加25-43例新的肝细胞癌病例，在过去的几年里以稳定的速度运行 过去6年。更准确地识别肝细胞癌高危人群和治疗早期肝细胞癌的更好策略是 控制这种发病率/死亡率是非常必要的。PD1阻断是一种新兴的治疗方法，虽然它对T细胞具有作用 在PD1阻断的中介作用已经被定义，对NK细胞活性的作用还不是很明确。同时 当NK细胞是肝脏内占主导地位的淋巴细胞时，已知NK细胞有助于控制 丙型肝炎病毒感染本身，而NK细胞具有抗癌效应。我们将遵循我们良好的性格 丙型肝炎病毒感染者人群采用NK细胞途径为重点的方法评价抗肿瘤宿主 丙型肝炎病毒相关肝细胞癌诊断前的免疫反应，以帮助识别预测标志物和 新的治疗策略。我们推测NK细胞在抵抗丙型肝炎病毒的宿主防御中起着不可或缺的作用。 相关的肝细胞癌，通过调节干扰素选择性增强NK细胞免疫功能 反应或PD1信号可被利用来提高宿主抗肝癌免疫，具有治疗潜力。 在肝癌诊断前确定NK细胞免疫将告知何时以及如何最好地告知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病的生物标志物。我们将对此进行调查 假设的目的如下：目的1：确定PD1在NK细胞增殖和抗肝癌中的作用 活动。目的2：确定选择性靶向长非编码RNA(LncRNA)NRIR的效果 (干扰素反应的负调节因子)增强干扰素依赖的抗肝癌活性。目标3： 明确NK细胞激活状态、功能、PD1途径参与和干扰素调节途径 在诊断为肝细胞癌之前的参与。

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.