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

项目总结 肝细胞癌是一个主要的健康问题，造成70多万人死亡 全球每年的死亡人数。尽管在过去的几十年里，肝细胞癌的治疗有了很大的进步，但大多数 被诊断为晚期的肝细胞癌患者没有资格接受肝等根治性消融治疗。 切除或移植。直到最近，FDA批准的针对这类患者的唯一疗法是 索拉非尼和瑞格拉非尼分别作为一线和二线治疗。不幸的是，这些 两种密切相关的多激酶抑制剂提供的生存益处有限。2017年9月， 尼伏卢单抗是一种PD-1(程序性细胞死亡1)免疫检查点抑制剂，获得加速治疗 在第二阶段取得了令人振奋的结果后，FDA批准了肝癌的二线治疗 临床试验(NCT01658878)。尽管一些肝癌患者表现出前所未有的反应 Nivolumab，并不是所有的患者都有反应，这表明存在驱动对 抗PD-1治疗，并强调迫切需要确定生物标记物以优化患者选择 以及克服阻力的策略。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，促进免疫逃逸和传递 抵抗抗PD-1治疗，但也告知患者分层和克服策略 抵抗。我们的中心假设是特定的致癌信号通路在肝细胞癌中被激活 放大免疫逃避机制，从而削弱对抗PD-1治疗的反应。通过 使用我们最近创建的一种新的肝癌免疫监测小鼠模型，我们已经 最近发现CTNNB1(β-catenin)、PTEN和KMT2C(MLL3)这三个基因是经常发生的 在人类肝癌中发生改变，都参与了免疫逃逸，证明了该项目的可行性。 此外，CTNNB1的激活使其对抗PD-1的阻断具有抵抗力，并可能成为 患者排斥的生物标记物。在这里，通过结合这种新的小鼠模型，人类肝癌样本， 以及转录和免疫特征，我们将建立促进 肝细胞癌中的免疫逃逸、免疫逃逸的潜在机制及其对反应的影响 去接受抗PD-1治疗。

PROJECT SUMMARY 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.