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

项目总结 这项应用，“高渗透性和免疫原性的非病毒性肝癌的小鼠模型，适用于 《免疫检查点抑制剂的评价》，是对FOA PAR-17-245研究项目的回应 以提高哺乳动物模型在翻译研究中的适用性“。这个项目的目标是开发 准确、创新和免疫原性的小鼠肝细胞癌模型，非常接近于 人类非病毒性肝细胞癌的主要病原学及其致病、转录和基因组图谱。这些 病因包括非酒精性(NASH)和酒精性(ASH)脂肪性肝炎，以及2型糖尿病(T2D)。 尽管目前导致肝细胞癌发生的主要原因是乙型和丙型肝炎病毒(乙肝病毒、丙型肝炎病毒)。 感染，非病毒性肝癌预计将成为这种侵袭性癌症的主要形式在美国和欧洲 在不太遥远的未来。尽管非病毒性肝细胞癌的发病率及其相关死亡率持续增长 以令人震惊的速度，肝细胞癌治疗进展缓慢，令人失望。然而，最近，抑制剂 PD-1：PD-L1检查点被发现在肝癌治疗中比任何其他靶向或 过去使用的非靶向治疗。尽管如此，客观应答率在20%左右，有很多 未来还有改进的空间。这种改进取决于更好地理解免疫检查点如何 抑制导致肝细胞癌消退，并确定增强对这一新类别的反应的佐剂 毒品的问题。这两个目标都取决于人肝细胞癌免疫原性小鼠模型的可用性。我们 将寄望于我们最近在开发NASH驱动的免疫原性肝细胞癌小鼠模型方面的成功 响应PD-1/PD-L1阻断发展新的和改进的非病毒性肝癌小鼠模型 快速和同步的肿瘤发展，使它们对翻译研究非常有用。除了……之外 NASH驱动的肝癌，我们将开发新的ASH驱动的肝细胞癌的免疫原性模型。我们还将生成一个 产生同步化原位肿瘤的一系列小鼠肝癌来源的细胞系，其生长和 对治疗的反应可以通过活体成像进行监测。以确定并证明人类的关联性 在这些模型中，它们将受到广泛的基因组和转录组鉴定，并 免疫分析。这些分析的结果将与基因组和转录图谱进行比较 人类肝细胞癌使用创新的计算工具。将实现以下具体目标：1)使用MUP- NASH驱动肝癌的uPA模型比较不同NASH相关饮食的致癌效果；2)使用 MUP-uPA小鼠建立ASH诱导的不涉及HFD喂养的新的肝癌模型；3)比较 小鼠和人类肝癌的基因组、转录和免疫图谱；以及4)从 不同的小鼠肝癌模型将产生同步的原位肿瘤，这对药物测试是有用的。

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.