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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：
10581235
负责人：
Amaia Lujambio
金额：
$ 37.89万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581235
关键词：
Acceleration Address Affect Applications Grants BAY 54-9085 Biological Markers CTNNB1 gene Cessation of life Clinical Trials 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 Mus Mutation Nivolumab Oncogenes Oncogenic PIK3CG gene PTEN gene Parents Pathway interactions Patient Selection Patients Phase Phase II Clinical Trials Phenotype Primary carcinoma of the liver cells Refractory Resistance Sampling Signal Pathway T cell infiltration TP53 gene Tail Testing Transplantation Tumor Antigens Tumor Escape Tumor Immunity Tumor Suppressor Genes Veins anti-PD-1 anti-PD1 therapy bak protein beta catenin biomarker identification cancer cell cancer immunotherapy design experimental study genetic element human disease immunogenicity improved inhibitor liver cancer model mouse model neoplastic cell novel overexpression parent grant patient biomarkers patient stratification pembrolizumab programmed cell death protein 1 response targeted treatment transcriptomics tumor vector

项目摘要

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.

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，获得FDA加速批准用于肝癌治疗，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PI 3 K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， CTNNB 1（β-catenin）、PTEN和KMT 2C（MLL 3）这三个在人HCC中经常改变的基因，在免疫逃逸中的应用，证明了该项目的可行性。此外，CTNNB 1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。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mouse Models of Oncoimmunology in Hepatocellular Carcinoma.

DOI：
10.1158/1078-0432.ccr-19-2923
发表时间：
2020-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Bresnahan E;Lindblad KE;Ruiz de Galarreta M;Lujambio A
通讯作者：
Lujambio A

Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses Against Hepatocellular Carcinoma.

DOI：
10.3390/cancers12113397
发表时间：
2020-11-16
期刊：
Cancers
影响因子：
5.2
作者：
Silva L;Egea J;Villanueva L;Ruiz M;Llopiz D;Repáraz D;Aparicio B;Lasarte-Cia A;Lasarte JJ;Ruiz de Galarreta M;Lujambio A;Sangro B;Sarobe P
通讯作者：
Sarobe P

Diverse immune response of DNA damage repair-deficient tumors.

DNA损伤修复缺陷肿瘤的不同免疫反应。