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

肿瘤内在信号通路限制肝细胞癌的抗肿瘤免疫

基本信息

批准号：
10177960
负责人：
Amaia Lujambio
金额：
$ 38.77万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10177960
关键词：
Address Affect BAY 54-9085 Biological Markers CTNNB1 gene Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Diagnosis Excision Exclusion FDA approved Genes Genetic Transcription Genetically Engineered Mouse Grant Health Hepatocyte Human Immune Immune Evasion Immune checkpoint inhibitor Immune response Immune system Immunologic Surveillance Immunotherapy Impairment Liver MYC gene Malignant neoplasm of liver Modeling Mosaicism Mus Mutation Nivolumab Oncogenes Oncogenic PD-1 blockade PD-1 inhibitors PTEN gene Pathway interactions Patient Selection Patients Phase Phase II Clinical Trials Phase III Clinical Trials Phenotype Primary carcinoma of the liver cells Refractory Resistance Sampling Signal Pathway TP53 gene Tail Testing Transplantation Tumor Antigens Tumor Escape Tumor Immunity Tumor Suppressor Genes Tumor-infiltrating immune cells Veins anti-PD-1 anti-PD1 therapy base beta catenin cancer cell cancer immunotherapy design experimental study genetic element human disease immunogenicity improved inhibitor/antagonist mouse model neoplastic cell novel overexpression patient biomarkers patient stratification pembrolizumab programmed cell death protein 1 response targeted treatment transcriptomics tumor vector

项目摘要

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.

项目摘要肝细胞癌（HCC）代表了一个主要的健康问题，造成超过70万全世界每年死亡。尽管HCC治疗在过去几十年中大大改善，但大多数在高级阶段诊断的HCC患者不符合治疗性消融疗法（例如肝脏）切除或移植。直到最近，此类患者唯一的FDA批准疗法是索拉非尼和雷莫非尼分别用作一线和二线治疗。不幸的是，这些两种密切相关的多次激酶抑制剂可提供有限的生存益处。 2017年9月， Nivolumab是PD-1（程序性细胞死亡1）免疫切除剂抑制剂，被授予加速在II期获得的承诺结果之后临床试验（NCT01658878）。尽管有一些HCC患者显示出空前的反应 Nivolumab，并非所有患者都反应，表明存在抗药性的机制抗PD-1疗法，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抵抗的策略。其他肿瘤类型的研究表明，不同的肿瘤内在的致癌途径，例如PI3K或Wnt/β-catenin，可促进免疫逃脱和会议抵抗抗PD-1疗法，但也为患者分层和克服策略提供了信息反抗。我们的中心假设是在HCC中激活的特定致癌信号通路扩增免疫进化的机制，从而损害对抗PD-1治疗的反应。经过使用我们最近创建的新型HCC免疫监视的鼠标模型，我们有最近证明了CTNNB1（β-catenin），PTEN和KMT2C（MLL3），三个基因经常人类HCC的改变，参与了免疫环境，证明了该项目的可行性。此外，CTNNB1激活贡献对抗PD-1阻滞的抗性，并有可能作为一种用于患者排除的生物标志物。在这里，通过将这种新颖的鼠标模型（人类HCC样品）结合在一起，以及转录和免疫探索，我们将建立促进的信号传导途径免疫逃逸在HCC中，免疫逃逸的潜在机制及其对反应的影响进行抗PD-1治疗。