Immunosuppressive mechanisms responsible for development of non-viral liver cancer and control of its response to immune checkpoint inhibitors

导致非病毒性肝癌发生及其对免疫检查点抑制剂反应的控制的免疫抑制机制

• 批准号: 10247489
• 负责人: Anthony Boutros El-Khoueiry
• 金额: $ 72.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247489
• 关键词: Adaptive Immune System; Affect; Attenuated; Cancer Control; Cancer Etiology; Cell Adhesion Molecules; Cessation of life; Clinical; Clinical Research; Conduct Clinical Trials; Cost Savings; Cytotoxic T-Lymphocytes; Development; Diffusion; Doctor of Medicine; Doctor of Philosophy; Doctor of Veterinary Medicine; Drug Targeting; Ethanol; Etiology; Europe; Fibrosis; Generations; Goals; Heavy Drinking; Hepatic Stellate Cell; Hepatitis C virus; High Fat Diet; Human; Immune; Immune checkpoint inhibitor; Immunoglobulin A; Immunologic Surveillance; Immunooncology; Immunotherapeutic agent; Immunotherapy; Incidence; Investigation; Liquid substance; Liver; Liver Fibrosis; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Modeling; Molecular; Mus; Nivolumab; Obesity Epidemic; Oncologist; Outcome; PD-1 blockade; PD-1/PD-L1; PD-L1 blockade; PDL1 inhibitors; Pathogenesis; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacology; Plasma Cells; Pre-Clinical Model; Prevalence; Primary carcinoma of the liver cells; Procedures; Protocols documentation; Research Personnel; Research Project Grants; Resistance; Role; Serum; Source; Specimen; Steatohepatitis; Study models; Therapeutic; Time; Translations; Treatment Failure; adaptive immune response; cancer immunotherapy; chemical carcinogen; chemokine; chronic liver inflammation; effective therapy; endoplasmic reticulum stress; improved; innovation; interest; medical schools; member; mortality; mouse model; non-alcoholic; nonalcoholic steatohepatitis; novel; objective response rate; pre-clinical research; predicting response; prevent; problem drinker; programmed cell death ligand 1; programmed cell death protein 1; response; stellate cell; targeted treatment; therapy outcome; translational scientist; treatment response; tumor; tumorigenic

PROJECT SUMMARY This project will explore adaptive immune mechanisms that control development of hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths, and dictate its responsiveness to PD-1:PD-L1 checkpoint inhibitors. Our team, including Michael Karin, Ph.D. and Shabnam Shalapour, Ph.D. at UCSD School of Medicine and Hidekazu Tsukamoto, D.V.M., Ph.D. and Anthony El-Khoueiry, M.D. at USC Keck School of Medicine, represents an ideal blend of basic researchers, translational scientists and oncologists who are interested in HCC molecular pathogenesis and treatment, especially in HCC caused by non-alcoholic (NASH) and alcoholic (ASH) steatohepatitis. Although the US incidence of HCC and its associated mortality have nearly tripled in the past generation, insufficient effort has been made toward identification and development of innovative and effective HCC therapies. However, the ideal and timely confluence of basic preclinical research and applied clinical studies carried out by our team members has the potential to critically transform HCC treatment forever. Together we found that chronic liver inflammation results in suppression of HCC-protective immunosurveillance to support rapid malignant progression. This unique immunopathogenic mechanism renders HCC responsive to drugs that disrupt the PD-1:PD-L1 checkpoint, but even the impressive response seen thus far and the selection of patients who will benefit from this therapeutic approach can be further improved. Such improvements can only be achieved by a deeper understanding of the mechanisms through which PD-1:PD-L1 inhibitors act, the factors that determine their efficacy, and the causes of treatment failure. We will achieve these goals through integrated studies of clinical specimens collected by Dr. El-Khoueiry and sophisticated, faithful and robust mouse models of non-viral HCC developed by Drs. Tsukamoto, Shalapour, and Karin. The immune mechanisms that control NASH- and ASH-driven HCC development in these models are highly similar to those that operate in human patients. Using this integrated approach, we will pursue five specific aims: 1) determine whether serum IgA concentrations correlate with therapeutic response to PD-1 blockade in patients with non-viral HCC; 2) develop reliable mouse models of ASH-driven HCC; 3) compare the immunosuppressive mechanisms that contribute to development of NASH- and ASH-driven HCC and control their response to PD-L1 blockade; 4) determine whether excessive peritumoral fibrosis correlates with diminished response to PD-1 blockade in HCC patients; and 5) determine whether agents that inhibit or attenuate stellate cell activation potentiate the response to PD- 1/PD-L1 blockade in non-viral HCC. The successful completion of these studies will result in substantial improvements to HCC immunotherapy and will establish reliable procedures for identification of patients who are most likely to benefit from PD-1/PD-L1 targeting drugs, advances that will result in significant cost savings which may amount to hundreds of millions of dollars annually.

项目总结