Programmed cell death-1 blockade enhances response to stereotactic radiation in an orthotopic murine model of hepatocellular carcinoma
Programmed cell death-1 blockade enhances response to stereotactic radiation in an orthotopic murine model of hepatocellular carcinoma
复制标题
DOI：
10.1111/hepr.12789
复制
发表时间：
2017-06-01
影响因子：
4.2
通讯作者：
Newell, Pippa
中科院分区：
文献类型：
--
作者：
Friedman, David;Baird, Jason R.;Newell, Pippa
目的：小的孤立性肝细胞癌可通过立体定向放射治疗或其他肿瘤消融方法治愈，但70%以上的患者会出现局部和全身肿瘤复发。方法：在超声引导下将同基因肝癌细胞株(Hep-551c)直接注射到C57BL/6小鼠的肝脏内，然后在CT引导下利用小动物放射研究平台进行立体定向放射治疗肿瘤。结果：给予3个剂量250 mU g的抗程序性细胞死亡蛋白-1(αPD-1)抗体，同时进行3次30GY立体定向全身放射治疗，可降低肿瘤的生长速度，提高生存率(P<；0.05)。联合治疗与肿瘤中CD8(+)细胞毒性T细胞的增加有关；CD8 T细胞的耗尽消除了联合治疗的疗效。联合治疗还可诱导肿瘤浸润性巨噬细胞程序性死亡-1配体的表达，停止αPD-1治疗后肿瘤迅速生长。结论：联合治疗可增强肿瘤对立体定向放射治疗的反应。然而，这种联合疗法的疗效是短暂的，治疗诱导了获得性免疫抵抗的标记。这些数据是有希望的，但也表明，这种组合需要持久地克服免疫耐药的机制，以产生持久的免疫力，以防止肿瘤复发。
Aim: Small, solitary hepatocellular carcinoma is curable with stereotactic radiation or other methods of tumor ablation, however, regional and systemic tumor recurrence occurs in over 70% of patients. Here we describe the ability of immunoradiotherapy to induce an antitumor immune response and delay the growth of tumors in immunocompetent mice.Methods: A syngeneic hepatocellular carcinoma cell line (Hep-55.1c) was injected directly into the livers of C57BL/6 mice using ultrasound guidance, then tumors were treated with stereotactic radiation using a Small Animal Radiation Research Platform with computed tomography guidance.Results: Delivery of three doses of 250 mu g anti-programmed cell death protein-1 (alpha PD-1) antibody concurrently with 30 Gy stereotactic body radiation therapy in three fractions reduced the growth rate of tumors and improved survival (P < 0.05). Combined treatment was associated with increased CD8(+) cytotoxic T cells in the tumor; depletion of CD8 T cells eliminated the efficacy of combined treatment. Combined treatment also induced expression of programmed cell death-1 ligand expression on tumor-infiltrating macrophages, and the tumors grew rapidly after alpha PD-1 treatment was discontinued.Conclusions: Tumor response to stereotactic radiation can be augmented by concurrent treatment with alpha PD-1. The efficacy of this combination therapy was transient, however, and treatment induced markers of adaptive immune resistance. These data are promising, but also indicate that mechanisms of immune resistance will need to be durably overcome for this combination to generate lasting immunity to protect against tumor recurrence.