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

项目摘要 肝细胞癌（HCC）是一个主要的健康问题，造成超过70万人死亡。 全球每年死亡人数。虽然HCC治疗在过去几十年中有了很大的改善，但大多数 诊断为晚期的HCC患者不适合进行根治性消融治疗，例如肝切除。 切除或移植。直到最近，FDA批准的治疗此类患者的唯一方法是 索拉非尼和瑞格非尼，分别用作一线和二线治疗。可惜这些 两种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是一种PD-1（程序性细胞死亡1）免疫检查点抑制剂， FDA批准用于HCC二线治疗，在II期获得有希望的结果后， 临床试验（NCT 01658878）。尽管一些HCC患者表现出前所未有的反应， 纳武利尤单抗，并非所有患者都有反应，表明存在驱动耐药的机制。 抗PD-1治疗，并强调迫切需要识别生物标志物以进行最佳患者选择 和克服阻力的策略。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， 抗PD-1治疗的耐药性，而且还告知患者分层和克服的策略 阻力我们的中心假设是肝癌中激活的特定致癌信号通路 增强免疫逃避机制，从而削弱对抗PD-1治疗的应答。通过 使用我们最近创建的一种新的HCC免疫监视小鼠模型，我们 最近研究表明，CTNNB1（β-catenin）、PTEN和KMT2C（MLL3）这三个基因经常被用于 在人类HCC中发生改变，参与免疫逃逸，证明了该项目的可行性。 此外，CTNNB1激活赋予对抗PD-1阻断的抗性，并且可能潜在地用作抗PD-1抗体。 排除患者的生物标志物。在这里，通过结合这种新的小鼠模型，人类HCC样本， 以及转录和免疫分析，我们将建立信号通路， HCC中的免疫逃逸，免疫逃逸的潜在机制及其对应答的影响 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.