Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance
Virus-induced hepatocellular carcinomas cause antigen-specific local tolerance
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DOI：
10.1172/jci64742
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发表时间：
2013-03-01
影响因子：
15.9
通讯作者：
Blankenstein, Thomas
中科院分区：
文献类型：
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作者：
Willimsky, Gerald;Schmidt, Karin;Blankenstein, Thomas
T细胞监视通常对病毒相关肿瘤有效，因为它们具有高免疫原性。目前尚不清楚为什么监测偶尔失败，特别是对B型肝炎病毒或丙型肝炎病毒相关的肝细胞癌（HCC）。我们建立了一个转基因小鼠模型的病毒诱导肝癌的肝细胞特异性腺病毒诱导的致癌SV 40大T抗原（TAg）的激活。腺病毒感染诱导针对病毒和TAg的细胞毒性T淋巴细胞（CTL），导致感染细胞的清除。尽管存在功能性抗原特异性T细胞，但少数病毒感染的细胞逃脱了免疫清除并进展为HCC。这些细胞表达的TAg水平与从新生的TAg耐受小鼠中分离的HCC相似，表明CTL清除不会选择具有低免疫原性的细胞。病毒感染的小鼠显示早期HCC中的T细胞浸润显著大于晚期HCC中的T细胞浸润，表明通过低效的T细胞浸润进行性局部免疫抑制。程序性细胞死亡蛋白-1（PD-1）及其配体PD-L1分别在所有TAG特异性CD 8（+）T细胞和HCC中表达，这有助于局部肿瘤抗原特异性耐受。因此，我们开发了一种病毒诱导的HCC模型，可以更好地了解人类HCC。
T cell surveillance is often effective against virus-associated tumors because of their high immunogenicity. It is not clear why surveillance occasionally fails, particularly against hepatitis B virus- or hepatitis C virus-associated hepatocellular carcinoma (HCC). We established a transgenic murine model of virus-induced HCC by hepatocyte-specific adenovirus-induced activation of the oncogenic SV40 large T antigen (TAg). Adenovirus infection induced cytotoxic T lymphocytes (CTLs) targeted against the virus and TAg, leading to clearance of the infected cells. Despite the presence of functional, antigen-specific T cells, a few virus-infected cells escaped immune clearance and progressed to HCC. These cells expressed TAg at levels similar to HCC isolated from neonatal TAg-tolerant mice, suggesting that CTL clearance does not select for cells with low immunogenicity. Virus-infected mice revealed significantly greater T cell infiltration in early-stage HCC compared with that in late-stage HCC, demonstrating progressive local immune suppression through inefficient T cell infiltration. Programmed cell death protein-1 (PD-1) and its ligand PD-L1 were expressed in all TAg-specific CD8(+) T cells and HCC, respectively, which contributed to local tumor-antigen-specific tolerance. Thus, we have developed a model of virus-induced HCC that may allow for a better understanding of human HCC.