A Multidisciplinary and Translational Approach to Hepatobiliary Malignancy

描述(申请人提供)：总而言之，肝癌是导致癌症死亡的第三大常见原因，也是美国所有癌症中死亡率增长最快的。这种癌症的治疗选择有限，尽管现代化疗取得了进步，但肝脏肿瘤患者的长期前景仍然极其黯淡。人们一直致力于研究肝癌的发生和发展机制，以期开发出早期诊断和新的治疗策略的生物标记物。为了开发合理的免疫学策略来治疗肝脏恶性肿瘤，重要的是要表征潜在的宿主-肿瘤相互作用。我们的初步数据表明，肝细胞癌存在无效的免疫反应，其特征是CD反应减弱，循环中的CD4CD25FoxP3调节性T细胞(Treg)和可溶性CD25的数量增加。我们发现肝细胞癌患者外周血中Tregs水平升高，抑制功能增强，且与肝细胞癌分期和肿瘤负荷有关。此外，存在T细胞抑制的总体水平(基于CD4T细胞增殖分析)，并且与可溶性CD25和总的肿瘤负荷密切相关。可溶性CD25是一种潜在的简单的、基于酶联免疫吸附试验的生物标志物，存在于T细胞活化的血清中(活化时从T和NK细胞中分离出sCD25)，因为最近的证据表明在肿瘤相关的免疫抑制中起作用。在这一应用中，我们将解决这一假设，即肝癌患者外周血中Tregs和CD25增加，并通过抑制细胞介导的CD4和CD8T细胞反应促进肝癌的发生/发展，而Tregs和/或sCD25的缺失将增强抗肝癌的细胞免疫。在特定的目标1中，我们将直接评估人肝癌诱导sCD25的机制及其对免疫反应的调节。在具体目标1中，我们还将评估我们的假设在发生肝癌的患者中，并将sCD25水平和Treg频率/功能与肝细胞癌的发生、进展和治疗反应相关联。我们提出的研究将为Tregs在肝癌中的作用提供重要的见解。更重要的是，使用一个具有良好特征的肝癌患者队列和一个具有良好特征的动物模型，我们将能够开发出新的肝癌诊断和治疗策略。在特定的目标2中，我们将表征TRAIL及其死亡受体DR4和DR5在人肝癌组织中的表达，确定TRAIL激动剂对切除肿瘤组织培养的人肝癌细胞的疗效，并利用HGS-ETR启动肝癌患者的临床试验。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激动剂在人类肝癌中的治疗潜力的研究。我们的体外和体内研究结果将为TRAIL激动剂对人体器官系统的全球影响提供关键的见解，这是广泛临床应用的基本数据。 公共卫生相关性：总之，这个K24应用程序建议支持一个独特的指导和培训计划，该计划在MD受训人员职业生涯的早期关键点识别和指导他们的胃肠/肿瘤/和肝胆外科。我已经制定了一份主题相关的提案，其中包括肝细胞癌分子和临床研究培训的课程作业和研究机会。

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.