Department of Pathology, Division of Biological Sciences and Moores Cancer Center, University of California at San Diego, La Jolla, CA.
Department of General Surgery, Second Affiliated Hospital of Zhejiang University, Hangzhou, P.R. China.
Hepatology. 2019 Jun;69(6):2518-2532. doi: 10.1002/hep.30528. Epub 2019 Mar 13.
Immunotherapy with checkpoint inhibitors for liver cancer, while active in many clinical trials worldwide, may have uncertain outcomes due to the unique immunotolerant microenvironment of the liver. In previous experiments, we unexpectedly identified a robust liver tumor-preventive effect of a synthetic double-stranded RNA, polyinosinic-polycytidylic acid (polyIC), in mice. Herein we further demonstrate that polyIC given at the precancer stage effectively prevented liver tumorigenesis by activating natural killer cells, macrophages, and some T-cell subsets; no inhibitory effect was observed on tumor progression if injected after tumor initiation. Nevertheless, polyIC administration potently induced programmed death ligand 1 (PD-L1) expression in liver sinusoid endothelial cells, which prompted us to test a combined treatment of polyIC and PD-L1 antibody (Ab). Although injecting PD-L1 Ab alone did not show any therapeutic effect, injection of polyIC sensitized the hepatic response to PD-L1 blockade. Combination of polyIC and PD-L1 Ab resulted in sustained accumulation of active cluster of differentiation 8 cytotoxic T cells and robust liver tumor suppression and conferred a survival advantage in mice. These preclinical data in animal models suggest that, despite the low efficacy of PD-L1/PD-1 blockade alone, careful design of mechanism-based combinatorial immunotherapeutic protocols may shift the paradigm in liver cancer treatment by coordinating maximal activation of multiple innate and adaptive immune functions. Conclusion: We provide proof of principle for the development of an efficient prevention strategy of liver tumorigenesis and a powerful combination immunotherapy for primary liver cancer.
免疫检查点抑制剂治疗肝癌在全球许多临床试验中都很活跃，但由于肝脏独特的免疫耐受微环境，其结果可能并不确定。在之前的实验中，我们意外地发现了一种合成双链 RNA，聚肌苷酸-聚胞苷酸（polyIC）在小鼠中具有强大的肝脏肿瘤预防作用。在此，我们进一步证明，在癌前阶段给予 polyIC 通过激活自然杀伤细胞、巨噬细胞和一些 T 细胞亚群，可有效预防肝肿瘤发生；如果在肿瘤起始后注射，则对肿瘤进展没有抑制作用。然而，polyIC 给药会强烈诱导肝窦内皮细胞中程序性死亡配体 1（PD-L1）的表达，这促使我们测试 polyIC 和 PD-L1 抗体（Ab）的联合治疗。虽然单独注射 PD-L1 Ab 没有显示出任何治疗效果，但注射 polyIC 使肝脏对 PD-L1 阻断的反应变得敏感。polyIC 和 PD-L1 Ab 的联合使用导致活性分化簇 8 细胞毒性 T 细胞的持续积累，并显著抑制肝脏肿瘤生长，赋予小鼠生存优势。这些动物模型的临床前数据表明，尽管单独使用 PD-L1/PD-1 阻断的疗效较低，但基于机制的组合免疫治疗方案的精心设计可能通过协调多种先天和适应性免疫功能的最大激活来改变肝癌治疗的范例。结论：我们为开发有效的肝癌发生预防策略和原发性肝癌的强大联合免疫疗法提供了原理证明。
