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

项目摘要 本项目将探索控制肝细胞癌发展的适应性免疫机制 (HCC)是癌症相关死亡的主要原因，并决定了其对PD-1：PD-L1检查点的反应性 抑制剂的我们的团队，包括Michael Karin博士，Shabnam Shalapour博士加州大学圣地亚哥分校医学院 和冢本秀一，D.V.M.，博士和Anthony El-Khoueiry，医学博士在南加州大学凯克医学院， 代表了基础研究人员、转化科学家和肿瘤学家的理想组合，他们对以下方面感兴趣： HCC的分子发病机制和治疗，特别是在非酒精性（NASH）和酒精性 (ASH)脂肪性肝炎尽管美国HCC的发病率及其相关死亡率在2008年几乎增加了两倍， 在过去的几代人中，对识别和开发创新和 有效的HCC治疗。然而，基础临床前研究和应用的理想和及时的融合， 我们团队成员开展的临床研究有可能永远彻底改变HCC治疗。 我们共同发现，慢性肝脏炎症导致HCC保护性免疫监视功能受到抑制 以支持快速的恶性进展。这种独特的免疫病理机制使HCC对免疫应答反应。 破坏PD-1：PD-L1检查点的药物，但即使是迄今为止看到的令人印象深刻的反应和选择， 可以进一步提高受益于这种治疗方法的患者的比例。这种改进只能 通过更深入地了解PD-1：PD-L1抑制剂的作用机制， 决定其疗效和治疗失败的原因。我们将通过综合措施实现这些目标。 El-Khoueiry博士收集的临床标本和复杂、可靠和稳健的小鼠模型的研究 Tsukamoto、Shalapour和Karin博士开发的非病毒性HCC。免疫机制控制着 在这些模型中NASH和ASH驱动的HCC发展与在人类中运行的HCC发展高度相似。 患者使用这种综合方法，我们将追求五个具体目标：1）确定血清伊加是否 浓度与非病毒性HCC患者对PD-1阻断的治疗反应相关; 2） 可靠的ASH驱动的HCC小鼠模型; 3）比较有助于 NASH和ASH驱动的HCC的发展，并控制它们对PD-L1阻断的反应; 4）确定 过度的瘤周纤维化是否与HCC患者对PD-1阻断的反应减弱相关; 和5）确定抑制或减弱星状细胞活化的试剂是否增强对PD-1的应答。 1/PD-L1阻断非病毒性HCC。这些研究的成功完成将导致大量的 改善HCC免疫治疗，并将建立可靠的程序，用于识别 最有可能受益于PD-1/PD-L1靶向药物，这些进展将导致显著的成本节约， 每年可能高达数亿美元。

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.