Tumor-intrinsic signaling pathways restrict anti-tumor immunity in hepatocellular carcinoma

项目摘要（来自母公司申请） 肝细胞癌（HCC）是一个主要的健康问题，导致超过70万人死亡 每年在世界各地。尽管HCC治疗在过去几十年中有了很大的改善，但大多数HCC患者 诊断为晚期的患者不适合进行根治性消融治疗，如肝切除术或 移植直到最近，FDA批准的用于此类患者的唯一治疗方法是索拉非尼， 瑞戈非尼，分别用作一线和二线治疗。不幸的是，这两个密切相关的 多激酶抑制剂提供有限的存活益处。2017年9月，nivolumab，一种PD-1（编程 细胞死亡1）免疫检查点抑制剂，被FDA加速批准用于HCC治疗， 二线，在II期临床试验（NCT 01658878）中获得有希望的结果后。尽管有一些HCC 患者对纳武单抗显示出前所未有的反应，但并非所有患者都有反应，这表明存在 导致抗PD-1治疗耐药的机制，并强调迫切需要识别生物标志物 最佳的病人选择和策略，以克服阻力。其他肿瘤类型的研究表明， 不同的肿瘤内源性致癌途径，如PI3K或WNT/β-catenin，促进免疫逃逸， 并赋予抗PD-1治疗的耐药性，但也告知患者分层和克服 阻力我们的中心假设是，在HCC中激活的特定致癌信号通路放大了 免疫逃避机制，从而损害对抗PD-1治疗的应答。通过使用一种新 我们最近建立的肝癌免疫监视小鼠模型，我们最近证明， CTNNB1（β-catenin）、PTEN和KMT2C（MLL3）这三个在人HCC中经常改变的基因， 在免疫逃逸中，证明了该项目的可行性。此外，CTNNB1激活赋予 抗PD-1阻断剂的抗性，并可能作为患者排除的生物标志物。这儿 结合这种新的小鼠模型，人类HCC样本，以及转录和免疫分析，我们将 建立促进HCC免疫逃逸的信号通路，免疫逃逸的潜在机制， 逃避，以及它们对抗PD-1治疗的反应的影响。

PROJECT SUMMARY (from parent application) Hepatocellular carcinoma (HCC) represents a major health problem, causing more than 700,000 deaths annually worldwide. Although HCC treatment has greatly improved over the last decades, most HCC patients diagnosed at advanced stages are ineligible for curative ablative therapies such as liver resection or transplantation. Until recently, the only FDA-approved therapies for such patients were sorafenib and regorafenib, used as first-line and second-line therapy, respectively. Unfortunately, these two closely related multikinase inhibitors provide limited survival benefits. In September 2017, nivolumab, a PD-1 (programmed cell death 1) immune checkpoint inhibitor, was granted accelerated approval by the FDA for HCC treatment in second line, after the promising results obtained in a phase II clinical trial (NCT01658878). Despite some HCC patients show unprecedented responses with nivolumab, not all patients respond, indicating the existence of mechanisms that drive resistance to anti-PD-1 therapy and highlighting the urgent need to identify biomarkers for optimal patient selection and strategies to overcome resistance. Studies in other tumor types demonstrate that different tumor-intrinsic oncogenic pathways, such as PI3K or WNT/β-catenin, promote immune escape and confer resistance to anti-PD-1 therapy but also inform patient stratification and strategies to overcome resistance. Our central hypothesis is that specific oncogenic signaling pathways activated in HCC amplify the mechanisms of immune evasion and thereby impair the response to anti-PD-1 therapy. By using a novel mouse model of HCC immune surveillance that we have recently created, we have recently demonstrated that CTNNB1 (β-catenin), PTEN, and KMT2C (MLL3), three genes frequently altered in human HCC, are involved in immune escape, demonstrating the feasibility of the project. Moreover, CTNNB1 activation confers resistance to anti-PD-1 blockade and could potentially serve as a biomarker for patient exclusion. Here, by combining this novel mouse model, human HCC samples, and transcriptional and immune profilings, we will establish the signaling pathways that promote immune escape in HCC, the underlying mechanisms of immune escape, and their effects on response to anti-PD-1 therapy.