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

• 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
• 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; 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

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.

项目摘要/摘要 肝细胞癌（HCC）是美国癌症相关死亡率的第六个主要原因， 由于慢性肝病及其相关的序列，正在上升。目前，对当前的响应率 由免疫检查点抑制剂（ICI）组成的治疗范式仍然很低，并且存在紧急 需要新颖的组合疗法以提高患者死亡率。缺乏对当前ICI的反应主要是 由于对肿瘤免疫微环境（时间）以及各种HCC驱动器的了解不足 突变导致特定的免疫表型。此外，目前没有生物标志物驱动 治疗治疗分层的治疗。 ꞵ-catenin-Active（由突变的CTNNB1癌基因编码）HCCS 约占HCC的大约26-35％ 免疫抑制时间和限制淋巴细胞对抗肿瘤免疫重要的效应功能。 我们已经开发了新型的ꞵ-catenin突变的HCC小鼠模型，其中突变体CTNNB1与 原始癌基因Met（ꞵ-catenin/hmet）或核因子红细胞2相关因子2（NRF2）（NRF2）（ꞵ---- catenin/nrf2）。这些模型分别占所有临床HCC病例的11％和10％。我们的初步 研究表明，ꞵ-catenin在ꞵ-catenin突变的HCC中增强了肿瘤发生，并且直接 靶向ꞵ-catenin促进驱动抗肿瘤免疫的炎症反应。基于这些 观察结果，我们的总体假设是ꞵ-catenin积极抑制适应性免疫反应 在时间和靶向ꞵ-catenin或其下游免疫调节因素可能会提高对 ICIS。为了调查，我提出了以下特定目标，这将发现ꞵ-catenin的新型机制 旨在开发精确医学疗法的HCC时间的信号传导。特定目标1：我们将 确定ꞵ-catenin抑制后激活的免疫细胞，并研究是否存在体内 通过单细胞RNA-severing（SCRNA-SEQ）和多路复用 免疫组织化学。这，我们将确定由ꞵ-catenin激活引起的免疫抑制的机制 在ꞵ-catenin突变的HCC中。特定目的2：根据我们的初步数据，显示了干扰素调节因子 - 2（irf2）在ꞵ-catenin突变的HCC中的表达，我们假设ꞵ-catenin-Mutated HCC可能是敏感的 在IRF2重新表达后，ICI，甚至显示出赞助的肿瘤回归 免疫反应。我们将使用合成生物学方法选择性地诱导IRF2表达 肿瘤发生和监测肿瘤负担的时间点。然后，我们将使用SCRNA-SEQ上的淋巴样种群 识别由IRF2调节的细胞类型和状态，以及IFNG（诱导IRF2） + ICI的测试组合 治疗方式。对培训的贡献：该建议结合了肝脏中严格的研究培训 癌症生物学，免疫肿瘤学和高级生物信息学分析具有出色的临床教育， 在癌症中免疫功能障碍的最前沿，帮助我作为未来的学术身体科学家的发展。