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

项目摘要(来自父应用程序) 肝细胞癌是一个重大的健康问题，导致70多万人死亡 每年在全球范围内。尽管在过去的几十年里，肝癌的治疗有了很大的改善，但大多数肝癌患者 诊断为晚期的患者没有资格接受根治性消融治疗，如肝切除或 移植。直到最近，FDA批准的用于此类患者的唯一疗法是索拉非尼和 瑞格非尼，分别作为一线和二线治疗。不幸的是，这两个密切相关 多激酶抑制剂提供的生存益处有限。2017年9月，尼伏卢单抗，PD-1(程控) 细胞死亡1)免疫检查点抑制剂，被FDA批准加速用于肝癌治疗 第二行，在II期临床试验(NCT01658878)取得有希望的结果后。尽管有一些肝细胞癌 患者对nivolumab的反应前所未有，但并不是所有患者都有反应，这表明存在 导致抗PD-1治疗耐药的机制，并强调迫切需要确定生物标志物 以获得最佳的患者选择和克服耐药性的策略。对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-连环蛋白，促进免疫逃逸 并赋予抗PD-1治疗的抵抗力，但也提供了患者分层和克服策略 抵抗。我们的中心假设是，在肝癌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治疗的反应。通过使用一本小说 我们最近建立的肝癌免疫监视的小鼠模型，我们最近已经证明 CTNNB1(β-catenin)、PTEN和KMT2C(MLL3)是三个在人肝细胞癌中经常改变的基因 在免疫逃逸方面，论证了该项目的可行性。此外，CTNNB1激活授权 对抗PD-1阻断的抵抗性，并可能成为患者排斥的生物标志物。在这里，由 结合这一新的小鼠模型、人类肝癌样本以及转录和免疫图谱，我们将 建立促进肝细胞癌免疫逃逸的信号通路，即免疫的潜在机制 逃逸，及其对抗PD-1治疗反应的影响。

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.