Investigating Immunosuppression in Beta-catenin-mutated Hepatocellular Carcinoma for Improved Precision Medicine Therapeutics

研究β-连环蛋白突变肝细胞癌的免疫抑制以改进精准医学治疗

基本信息

批准号：
10749344
负责人：
Brandon Lehrich
金额：
$ 5.27万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749344
关键词：
Antigen Presentation Automobile Driving Award BAY 54-9085 Binding Bioinformatics Biological Response Modifiers CTNNB1 gene Cancer Biology Cancer Etiology Cell Proliferation Cells Clinical Combined Modality Therapy Data Development Disease Education Exclusion Future Gene Expression Genes Growth Immune Immune System Diseases Immune Targeting Immune checkpoint inhibitor Immune response Immunohistochemistry Immunooncology Immunosuppression Immunotherapeutic agent Immunotherapy Incidence Inflammatory Response Injections Interferon Regulatory Factor 2 K-Series Research Career Programs Knock-out Lead Link Liver Lymphocyte Lymphocyte Activation Lymphocyte Function Lymphoid MET gene Malignant Neoplasms Malignant neoplasm of liver Modality Modeling Monitor Mutate Oncogenes Patients Phenotype Physicians Population Predisposition Primary carcinoma of the liver cells Proto-Oncogenes Receptor Protein-Tyrosine Kinases Regimen Regulation Repression Research Training Residencies Resistance Role Scientist Signal Transduction Sleeping Beauty Survival Rate System Tail Techniques Testing Therapeutic Therapeutic Effect Training Transposase Tumor Burden Tumor Immunity Tumor-infiltrating immune cells United States Unresectable Veins adaptive immune response anti-PD1 therapy beta catenin biomarker driven career cell type chronic liver disease clinically relevant combinatorial differential expression driver mutation end stage disease immunoregulation improved in vivo inhibitor liver cancer model molecular subtypes mortality mouse model mutant mutant mouse model neoplastic cell novel nuclear factor-erythroid 2 objective response rate precision medicine response response biomarker single-cell RNA sequencing standard of care synergism synthetic biology transcription factor treatment stratification tumor tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Hepatocellular carcinoma (HCC) is the 6th leading cause of cancer-associated mortality in the United States, and is rising due to chronic liver disease and its associated sequalae. Currently, the response rates to current therapeutic paradigms consisting of immune checkpoint inhibitors (ICIs) remain low, and there exist an urgent need for novel combinatorial therapies to improve patient mortality. Lack of response to current ICIs is mainly due to a poor understanding of the tumor immune microenvironment (TIME) and how various HCC driver mutations lead to specific immune phenotypes. Additionally, there currently exist no biomarker-driven therapeutics for patient treatment stratification. ꞵ-catenin-active (encoded by mutated CTNNB1 oncogene) HCCs represent approximately 26-35% of HCCs and respond poorly to ICIs due to ꞵ-catenin driving an immunosuppressive TIME and limiting the effector function of lymphocytes important for anti-tumor immunity. We have developed novel ꞵ-catenin-mutated HCC mouse models where mutant CTNNB1 is co-expressed with either the proto-oncogene MET (ꞵ-catenin/hMet) or nuclear factor erythroid 2–related factor 2 (Nrf2) (ꞵ- catenin/Nrf2). These models represent 11% and 10% of all clinical HCC cases, respectively. Our preliminary studies demonstrate that ꞵ-catenin potentiates tumorigenesis in ꞵ-catenin-mutated HCC, and that directly targeting ꞵ-catenin promotes an inflammatory response driving anti-tumor immunity. Based on these observations, our overarching hypothesis is that ꞵ-catenin actively suppresses the adaptive immune response in the TIME and targeting ꞵ-catenin or its downstream immunomodulatory factors may improve susceptibility to ICIs. To investigate, I propose the following specific aims, which will uncover novel mechanisms of ꞵ-catenin signaling in the HCC TIME, aimed at developing precision medicine therapeutics. Specific Aim 1: We will determine the immune cells activated following ꞵ-catenin inhibition, and investigate whether there is in vivo synergy combining ꞵ-catenin inhibition and ICIs through single-cell RNA-sequencing (scRNA-seq) and multiplex immunohistochemistry. Thus, we will identify mechanisms of immunosuppression caused by ꞵ-catenin activation in ꞵ-catenin-mutated HCC. Specific Aim 2: Based on our preliminary data showing interferon regulatory factor- 2 (IRF2) repression in ꞵ-catenin-mutated HCC, we hypothesize that ꞵ-catenin-mutated HCCs may be sensitized to ICIs, or even show spontaneous tumor regression, upon re-expression of IRF2 as a result of enhanced immune response. We will use synthetic biology approaches to selectively induce IRF2 expression at various timepoints in tumorigenesis and monitor tumor burden. We will then use scRNA-seq on the lymphoid population to identify cell types and states regulated by IRF2, and test combination of IFNg (which induces IRF2) + ICI as a therapeutic modality. Contribution to Training: This proposal combines rigorous research training in liver cancer biology, immuno-oncology, and advanced bioinformatic analyses with an excellent clinical education, to aid my development as a future academic physician-scientist at the forefront of immune dysfunction in cancer.

项目概要/摘要肝细胞癌 (HCC) 是美国癌症相关死亡的第六大原因，由于慢性肝病及其相关后遗症，目前的反应率正在上升。由免疫检查点抑制剂（ICIs）组成的治疗范式仍然很低，并且存在紧迫的问题需要新的组合疗法来降低患者死亡率的主要原因是对当前 ICI 缺乏反应。由于对肿瘤免疫微环境 (TIME) 以及各种 HCC 驱动因素了解甚少此外，目前还没有生物标志物驱动的突变导致特定的免疫表型。用于患者治疗分层的疗法。ꞵ-连环蛋白活性（由突变的 CTNNB1 癌基因编码）HCC。约 26-35% 的 HCC 因 ꞵ-catenin 驱动而对 ICI 反应不佳免疫抑制时间和限制淋巴细胞的效应功能对于抗肿瘤免疫很重要。我们开发了新型 ꞵ-catenin 突变 HCC 小鼠模型，其中突变型 CTNNB1 与原癌基因 MET (ꞵ-catenin/hMet) 或核因子红细胞 2 相关因子 2 (Nrf2) (ꞵ- 连环蛋白/Nrf2）。这些模型分别占我们初步的所有临床 HCC 病例的 11% 和 10%。研究表明 ꞵ-catenin 增强 ꞵ-catenin 突变的 HCC 中的肿瘤发生，并且直接基于这些，靶向 ꞵ-连环蛋白可促进炎症反应，从而驱动抗肿瘤免疫。根据观察，我们的总体假设是 ꞵ-catenin 主动抑制适应性免疫反应在 TIME 中并靶向 ꞵ-catenin 或其下游免疫调节因子可能会提高对为了进行研究，我提出了以下具体目标，这将揭示 ꞵ-catenin 的新机制。 HCC TIME 中的信号传导，旨在开发精准医学疗法。具体目标 1：我们将。确定 ꞵ-catenin 抑制后激活的免疫细胞，并研究体内是否存在通过单细胞 RNA 测序 (scRNA-seq) 和多重分析将 ꞵ-catenin 抑制与 ICI 结合起来产生协同作用因此，我们将确定 ꞵ-连环蛋白激活引起的免疫抑制机制。具体目标 2：根据我们显示干扰素调节因子的初步数据- 2 (IRF2) 在 ꞵ-catenin 突变的 HCC 中受到抑制，我们认为 ꞵ-catenin 突变的 HCC 可能会敏感由于 IRF2 的增强而重新表达，从而导致 ICI 的发生，甚至表现出自发的肿瘤消退。我们将使用合成生物学方法选择性诱导IRF2在不同部位的表达。然后我们将在淋巴群体上使用 scRNA-seq。鉴定受 IRF2 调节的细胞类型和状态，并测试 IFNg（诱导 IRF2）+ ICI 的组合作为对培训的贡献：该提案结合了严格的肝脏研究培训。癌症生物学、免疫肿瘤学和先进的生物信息分析以及优秀的临床教育，帮助我发展成为一名未来的学术医师科学家，处于癌症免疫功能障碍的最前沿。