Tumor antigen-specific T-cells and hepatocellular carcinoma

描述（由申请人提供）：在美国，由于丙型肝炎感染者的年龄增长、感染持续时间和疾病分期，肝细胞癌的医疗负担继续增加。肝细胞癌已被证明表达潜在的免疫原性蛋白，如甲胎蛋白和甘聚糖-3。然而，病理上在HCC内部或周围很少能检测到t细胞，这表明体内对这些抗原特异性的t细胞的抗原识别、扩增、归巢和/或效应功能受到抑制。我们假设肿瘤抗原特异性CD8+ T细胞具有完整的增殖能力并发挥多种效应功能，但在肝硬化患者中存在，但在自然发展为肝细胞癌的过程中，由于肿瘤微环境的抑制而发生严重的功能损伤。我们的目标是证明我们可以有效地从非荷瘤肝硬化患者的外周血淋巴细胞中扩增多功能肿瘤抗原特异性CD8+ t细胞，目的是最终证明在HCC发病前启动和扩增这些t细胞可以延缓或预防肝细胞癌的发病。我们将首先通过检查肿瘤消融对HCC患者肿瘤抗原特异性CD8+ t细胞的作用来验证这一假设。通过研究抑制性共刺激阻断对肿瘤浸润性t细胞的影响

DESCRIPTION (provided by applicant): The medical burden of hepatocellular carcinoma continues to increase in the United States as a consequence of the progressing age, duration of infection, and thus disease stage of hepatitis C-infected individuals. Hepatocellular carcinoma has been shown to express potentially immunogenic proteins such as alpha-fetoprotein and glypican-3. However, few if any T-cells can be detected in or around HCC pathologically, suggesting that the antigen recognition, expansion, homing and/or effector function of T-cells specific for these antigens have been suppressed in vivo. We hypothesize that tumor antigen-specific CD8+ T cells with intact capacity to proliferate and exert multiple effector functions exit in cirrhotic patients but in the natural progression to hepatocellular carcinoma develop profound functional impairment due to the suppressive tumor microenvironment. Our goal is to demonstrate that we can efficiently expand polyfunctional tumor antigen-specific CD8+ T-cells from peripheral blood lymphocytes from non-tumor-bearing cirrhotic patients with the intent of ultimately proving that priming and expanding these T-cells prior to the onset of HCC may retard or prevent the onset of hepatocellular carcinoma. We will approach this hypothesis first by examining the role of tumor ablation on tumor antigen-specific CD8+ T-cells from HCC patients. By studying the effects of inhibitory co-stimulation blockade on tumor-infiltrating T-cells and the longitudinal effects of intratumoral ablation on tumor-specific T-cells, we will precisely define te critical mechanisms involved in tumor-induced T-cell suppression in HCC. Secondly, we will attempt to demonstrate that highly functional cytolytic CD8+ effector T-cells targeting tumor antigens can be expanded from peripheral blood lymphocytes of cirrhotic patients at risk for future hepatocellular carcinoma but in whom cancer has yet to develop. Lastly, we will evaluate a cell-based vaccine platform to stimulate hepatoma-specific T-cells, as a platform toward developing a novel, preventive vaccine. The ultimate goal of these studies is to develop pre-clinical validation to support translation of cell-based vaccination into human clinical trials to prevent or delay the development of hepatocellular carcinoma in cirrhosis.