A new mouse model for studying the pathogenesis and immunobiology of intrahepatic cholangiocarcinoma and improving its immunotherapy

研究肝内胆管癌发病机制和免疫生物学并改进其免疫治疗的新小鼠模型

• 批准号: 10711615
• 负责人: Michael Karin
• 金额: $ 56.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711615
• 关键词: Accounting; Alcohol abuse; Biliary; CD8-Positive T-Lymphocytes; Cell Communication; Cell Nucleus; Cell Surface Receptors; Cells; Characteristics; Cholestasis; Clinical; Clinical Management; Complement; Complication; Data; Desmoplastic; Diagnosis; Differential Diagnosis; Early Diagnosis; Epigenetic Process; Evaluation; Evolution; Exclusion; Exhibits; Failure; Fibroblasts; Goals; Hepatobiliary; Hepatocyte; High Fat Diet; Human; Immune; Immune checkpoint inhibitor; Immunobiology; Immunocompetent; Immunophenotyping; Immunosuppression; Immunotherapy; Incidence; Inflammatory Bowel Diseases; Intraepithelial Neoplasia; Intrahepatic Cholangiocarcinoma; KDR gene; Lesion; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Modeling; Molecular; Mus; Mutation; Myeloid-derived suppressor cells; Nodule; Non-Insulin-Dependent Diabetes Mellitus; Oncogenic; Pathogenesis; Pathologic; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Radiology Specialty; Reaction; Risk Factors; Signal Transduction; Study models; Survival Rate; T cell receptor repertoire sequencing; T-Lymphocyte; T-cell receptor repertoire; Techniques; Therapeutic; Transcriptional Activation; Translating; Tumor-Infiltrating Lymphocytes; Variant; Vegf Inhibitor; biliary tract; cancer cell; cancer type; checkpoint inhibition; cholangiocyte; endoplasmic reticulum stress; experimental study; immunogenic; improved; information gathering; inhibitor; mouse model; neoplastic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; overexpression; pressure; prevent; progenitor; regenerative; response; tobacco abuse; transcription factor; transcriptomics; tumor; tumor microenvironment; tumor-immune system interactions

ABSTRACT Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer (PLC) that is particularly hard to treat, having an overall 5-year survival rate of 8%. Like the major PLC, hepatocellular carcinoma (HCC), ICC incidence is on the rise due to the ongoing increase in cholestatic liver diseases, non-alcoholic fatty liver diseases, type 2 diabetes and alcohol and tobacco abuse. Unlike HCC, ICC is often detected at an advanced stage when survival prospects are poor, a complication of its imprecise differentiation from early HCC by current radiological techniques. Early differential diagnosis of two PLCs is critical due to their distinct management and the absence of targetable oncogenic drivers shared by ICC and HCC. This problem could be solved by identification of a PLC- type agnostic therapeutic approach, such as immune checkpoint inhibition (ICI), that is applicable to both ICC and HCC. However, while ICI based therapies were approved for HCC and their efficacy has been improved by combination with VEGF inhibitors, they have performed poorly in ICC. This failure can be attributed, in part, to poor mechanistic understanding of the ICC-specific immunosuppressive tumor microenvironment (TME) and lack of suitable mouse models that allow the evaluation of ICI in combination with therapeutics capable of dismantling immunosuppression. We have solved this problem by developing a new ICC model that unlike previous mouse models does not depend on forced overexpression of potent oncogenic drivers that rapidly induce ICC in the absence of selective pressure for acquisition of additional mutations. Our MUP-uPA/NRF2Act model depends on combination of ER stress with activation of transcription factor NRF2 in bipotential hepatobiliary progenitors and mature hepatocytes and shows robust, highly penetrant, human-like stepwise progression towards ICC that is accompanied by the buildup of an immunosuppressive TME exhibiting CD8+ T cell exclusion. We plan to establish the MUP-uPA/NRF2Act mouse as the leading model for studying the evolution of ICC and its immunosuppressive TME and for finding treatments that will dismantle immunosuppression and boost the response to existing PD-(L)1 inhibitors. To accomplish this goal, we will fully characterize the MUP- uPA/NRF2Act mouse, defining the transcriptomic, epigenetic, and genetic alterations at each stage of ICC progression, including ductular reactions, biliary intraepithelial neoplasia and established desmoplastic cancer. We will also define the T cell receptor (TCR) repertoire of tumor infiltrating lymphocytes at each stage of malignant progression and mine the transcriptomic data for cancer cell produced factors that mediate desmoplasia, immunosuppression and CD8+ T cell exclusion. These studies will be complemented by immunophenotyping and immunodepletion experiments whose goal is the identification of targetable molecular switches responsible for establishment of the ICC-specific immunosuppressive TME. We will use this information to identify clinically approved treatments that can overcome immunosuppression and vastly improve the efficacy of ICI therapy based on PD-(L)1 inhibitors.

摘要