Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, The Netherlands.
Hepatology. 2013 Jan;57(1):183-94. doi: 10.1002/hep.26013. Epub 2012 Dec 4.
The mechanisms that enable liver cancer to escape elimination by the immune system remain unclear, but their elucidation may provide novel therapeutic interventions. We investigated the influence of tumor-infiltrating regulatory T cells on tumor-specific T cell responses in patients with liver cancer, using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC). Here we report that in both HCC and LM-CRC, CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in the tumor milieu and are potent suppressors of autologous tumor-specific T cell responses. Especially in LM-CRC, where Treg accumulation is more prominent, there is good evidence for local proliferation of Tregs at the cancer site. We show that tumor Tregs up-regulate the expression of glucocorticoid-induced tumor necrosis factor receptor (GITR) compared with Tregs in tumor-free liver tissue and blood. Importantly, treatment with soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor-infiltrating Tregs and restores the proliferative capacity and cytokine production of CD4+CD25- T cells.
Our results show that tumor-associated Tregs are critical for immune evasion in liver cancer, and we propose that GITRL constitutes a rational treatment for this disease.
使肝癌逃避免疫系统清除的机制仍不清楚，但阐明这些机制可能为新的治疗干预提供依据。我们研究了肿瘤浸润调节性 T 细胞对肝癌患者肿瘤特异性 T 细胞反应的影响，使用来自肝细胞癌（HCC）或结直肠癌肝转移（LM-CRC）个体的体外分离细胞。在这里，我们报告在 HCC 和 LM-CRC 中，CD4+CD25+Foxp3+调节性 T 细胞（Tregs）在肿瘤微环境中积累，并强烈抑制自体肿瘤特异性 T 细胞反应。特别是在 LM-CRC 中，Treg 的积累更为明显，有充分的证据表明 Treg 在癌症部位局部增殖。我们表明，与无肿瘤肝脏组织和血液中的 Tregs 相比，肿瘤 Tregs 上调了糖皮质激素诱导的肿瘤坏死因子受体（GITR）的表达。重要的是，用可溶性 GITR 配体（GITRL）治疗可降低激活的肿瘤浸润性 Tregs 介导的抑制作用，并恢复 CD4+CD25-T 细胞的增殖能力和细胞因子产生。
我们的结果表明，肿瘤相关的 Tregs 是肝癌免疫逃逸的关键，我们提出 GITRL 构成了治疗这种疾病的合理选择。
