Highly penetrant and immunogenic mouse models of non-viral HCC that are suitable for evaluation of immune checkpoint inhibitors

项目摘要 该申请，“高渗透性和免疫原性的非病毒性肝癌小鼠模型，适用于 免疫检查点抑制剂的评价”，是响应FOA PAR-17-245“研究项目”提交的 提高哺乳动物模型在转化研究中的适用性”。该项目的目标是开发 准确、创新和免疫原性的肝细胞癌（HCC）小鼠模型， 人类非病毒性肝癌的主要病因包括其致病性、转录组和基因组特征。这些 病因包括非酒精性（NASH）和酒精性（ASH）脂肪性肝炎和2型糖尿病（T2 D）。 虽然目前肝细胞癌发展的主要病因是肝炎病毒B和C（HBV，HCV） 在美国和欧洲，非病毒性HCC预计将成为这种侵袭性癌症的主要形式。 在不太遥远的将来。虽然非病毒性HCC的发病率及其相关死亡率持续增长， 以惊人的速度，HCC治疗的进展一直令人不安地缓慢。然而，最近， 发现PD-1：PD-L1检查点在HCC治疗中比任何其它靶向或 过去使用的非靶向治疗。尽管如此，客观答复率在20%左右， 未来改进的空间。这种改善取决于更好地理解免疫检查点如何 抑制导致HCC消退，并鉴定出增强对这种新类型应答的佐剂 毒品这两个目标都依赖于人HCC免疫原性小鼠模型的可用性。我们 我们最近成功开发了一种NASH驱动的HCC免疫原性小鼠模型， 对PD-1/PD-L1阻断有反应，以开发新的和改进的非病毒HCC小鼠模型， 快速和同步的肿瘤发展，使它们对转化研究非常有用。除了 NASH驱动的HCC，我们将开发新的免疫原性模型的ASH驱动的HCC。我们还将生成一个 一系列小鼠肝癌衍生的细胞系，产生同步原位肿瘤，其生长和 对治疗的反应可以通过体内成像来监测。为了确定和证明人类的相关性 在这些模型中，它们将受到广泛的基因组和转录组学表征， 免疫分析这些分析的结果将与以下的基因组和转录组谱进行比较： 人类肝癌的研究。将追求以下具体目标：1）使用内务部警察- NASH驱动的HCC的uPA模型，以比较不同NASH相关饮食的致癌功效; 2）使用 MUP-uPA小鼠开发不涉及HFD喂养的新的ASH诱导的HCC模型; 3）比较 小鼠和人HCC基因组、转录组和免疫谱;和4）从HCC中产生细胞系。 不同的小鼠HCC模型将产生用于药物测试的同步原位肿瘤。

PROJECT SUMMARY This application, “Highly penetrant and immunogenic mouse models of non-viral HCC that are suitable for evaluation of immune checkpoint inhibitors”, is submitted in response to FOA PAR-17-245 “Research Projects to Enhance Applicability of Mammalian Models for Translational Research”. The goal of this project is to develop accurate, innovative, and immunogenic mouse models of hepatocellular carcinoma (HCC) that closely mimic the main etiologies of human non-viral HCC in their pathogenic, transcriptomic, and genomic profiles. These etiologies include non-alcoholic (NASH) and alcoholic (ASH) steatohepatitis, and type 2 diabetes (T2D). Although the current major etiologies that underlie HCC development are hepatitis virus B and C (HBV, HCV) infections, non-viral HCC is predicted to become the major form of this aggressive cancer in the US and Europe in the not too distant future. While the incidence of non-viral HCC and its associated mortality continue to grow at an alarming rate, progress in HCC treatment has been disappointingly slow. Recently, however, inhibitors of the PD-1:PD-L1 checkpoint were found to be much more effective in HCC treatment than any other targeted or non-targeted therapeutic used in the past. Nonetheless, with objective response rates around 20%, there is much room for future improvement. Such improvement depends on better understanding of how immune checkpoint inhibition leads to HCC regression and the identification of adjuvants that enhance the response to this new class of drugs. Both objectives are dependent on the availability of immunogenic mouse models of human HCC. We will bank on our recent success in developing an immunogenic mouse model of NASH-driven HCC that is responsive to PD-1/PD-L1 blockade to develop new and improved mouse models of non-viral HCC that show rapid and synchronized tumor development, making them highly useful for translational research. In addition to NASH-driven HCC, we will develop new immunogenic models of ASH-driven HCC. We will also generate a series of mouse HCC-derived cell lines that give rise to synchronized orthotopic tumors, whose growth and response to treatment can be monitored by in vivo imaging. To determine and demonstrate the human relevance of these models, they will be subjected to extensive genomic and transcriptomic characterization and immunoprofiling. The results of these analyses will be compared to the genomic and transcriptomic profiles of human HCC using innovative computational tools. The following Specific Aims will be pursued: 1) Use the MUP- uPA model of NASH driven HCC to compare the carcinogenic efficacy of different NASH-related diets; 2) Use the MUP-uPA mouse to develop new models of ASH-induced HCC that do not involve HFD feeding; 3) Compare mouse and human HCC genomic, transcriptomic, and immune profiles; and 4) Generate cell lines from the different mouse HCC models that will give rise to synchronized orthotopic tumors that are useful for drug testing.