A Multidisciplinary and Translational Approach to Hepatobiliary Malignancy

概述（由申请人提供）：总之，HCC是癌症死亡的第三大常见原因，并且在美国的任何癌症中死亡率增长最快。这种癌症的治疗选择有限，尽管现代化疗取得了进展，但肝脏肿瘤患者的长期前景仍然非常糟糕。为了开发用于早期诊断和新的治疗策略的生物标志物，人们已经开展了大量的研究工作，以确定HCC的发生和发展机制。为了制定合理的免疫策略治疗肝脏恶性肿瘤，重要的是表征潜在的宿主-肿瘤相互作用。我们的初步数据表明，HCC存在无效的免疫应答，其特征是CD应答受损，循环CD4+CD25+ FoxP3调节性T细胞（Treg）和可溶性CD25数量增加。我们发现肝癌患者外周血中Tregs升高，抑制功能增强，与肝癌分期和肿瘤负荷相关。此外，T细胞抑制的总体水平（基于CD4 T细胞增殖测定）与可溶性CD25和总体肿瘤负荷密切相关。可溶性CD25在T细胞激活的血清中是一种潜在的简单的、基于elisa的“生物标志物”（sCD25在T细胞和NK细胞激活时被切割），因为最近的证据表明它在肿瘤相关的免疫抑制中起作用。在本应用中，我们将解决以下假设：HCC患者外周血中Tregs和CD25增加，并通过抑制细胞介导的CD4和CD8 T细胞反应促进HCC的发展/进展，而Tregs和/或sCD25的消耗会增强对HCC的细胞免疫。在Specific Aim 1中，我们将直接评估sCD25被人类HCC诱导和免疫反应调节的机制。在Specific Aim 1中，我们还将在发生HCC的患者中评估我们的假设，并将sCD25水平和Treg频率/功能与HCC的发生、进展和对治疗的反应联系起来。我们提出的研究将为Tregs在肝癌中的功能提供重要的见解。更重要的是，使用具有良好特征的HCC患者队列和具有良好特征的动物模型，我们将能够开发新的HCC诊断和治疗策略。在Specific Aim 2中，我们将表征TRAIL及其死亡受体DR4和DR5在人HCC组织中的表达，确定TRAIL激动剂对切除癌组织培养的人HCC细胞的疗效，并利用HGS-ETR在HCC患者中开展临床试验。这项研究（基于我们自己的研究数据发起）将是世界上第一个全面研究TRAIL激动剂对人类肝癌治疗潜力的研究。我们体外和体内研究的结果将为TRAIL激动剂对人体器官系统的整体影响提供关键见解，这是广泛临床应用的重要数据。

DESCRIPTION (provided by applicant): In summary, HCC is the third most common cause of cancer mortality and has the fastest growing mortality rate of any cancer in the US. There are limited treatment options for this cancer and despite the advance of modern chemotherapy, the long-term outlook for patients with liver tumors remains extremely poor. Intensive research efforts have been directed toward the identification of the mechanism of initiation and progression of HCC in hopes of developing biomarkers for early diagnosis and novel treatment strategies. In order to develop rational immunological strategies for treating liver malignancies, it is important to characterize the underlying host-tumor interactions. Our preliminary data suggests that there is an ineffective immune response to HCC, which is characterized by impaired CD response, increased populations of circulating CD4+CD25+ FoxP3 regulatory T cells (Treg) and soluble CD25. We found an elevation of Tregs with enhanced suppressive function in the peripheral blood of patients with HCC which correlated with stage and tumor burden of HCC. In addition, there was an overall level of T cell suppression (based on CD4 T cell proliferation assays) and a close relationship with soluble CD25 and overall tumor burden. Soluble CD25 represents a potential simple, ELISA-based "biomarker" in the serum of T cell activation (sCD25 is cleaved from T and NK cells on activation) and because recent evidence has suggested a role in tumor related immunosuppression. In this application, we will address the hypothesis that Tregs and CD25 are increased in peripheral blood of HCC patients and promote HCC development/progression via suppression of cell mediated CD4 and CD8 T cell responses, and depletion of Tregs and/or sCD25 would enhance cellular immunity against HCC. In Specific Aim 1 we will directly evaluate the mechanisms of sCD25 induction by human HCC and modulation of immune response. In Specific Aim 1, we will also evaluate our hypothesis in patients who develop HCC and will correlate the sCD25 levels and Treg frequency / function with HCC development, progression, and response to therapy. Our proposed study will provide critical insights into the function of Tregs in liver cancer. More importantly, using a well-characterized HCC patient cohort and a well characterized animal model, we will be able to develop novel diagnostic and therapeutic strategies for HCC. In Specific Aim 2, we will characterize the expression of TRAIL and its death receptor DR4 and DR5 in human HCC tissues, determine the efficacy of TRAIL agonists on human HCC cells cultured from resected cancer tissues, and initiate clinical trials in patients with HCC using HGS-ETR. This study (initiated based on our own research data) will be the first in the world to comprehensively investigate the therapeutic potential of TRAIL agonists in human liver cancer. The outcome of our in-vitro and in-vivo studies will provide critical insights into the global effect of TRAIL agonists on human organ systems, which is essential data for broad clinical applications. PUBLIC HEALTH RELEVANCE: In conclusion, this K24 application proposes to support a unique mentoring and training program that identifies and mentors MD trainees in gastroenterology /oncology/ and hepatobiliary surgery at an early critical point in their career. I have framed a thematically related proposal that includes coursework and research opportunities for molecular and clinical research training in hepatocellular carcinoma.