IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model
IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model
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DOI：
10.1016/j.bbrc.2017.02.128
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发表时间：
2017-04-29
影响因子：
3.1
通讯作者：
Lu, Kai
中科院分区：
文献类型：
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作者：
Liu, Hu;Shen, Jun;Lu, Kai
临床试验中观察到免疫检查点抑制剂对肝细胞癌的疗效有限，因此促使人们对联合治疗进行研究。白介素6(IL-6)在模拟肿瘤免疫反应中起着重要作用。在此，我们假设阻断IL-6将增强肝癌的抗肿瘤免疫，并与抗程序性死亡-1配体1(PD-L1)检查点抑制剂在治疗肝癌中具有协同作用。探讨IL-6在肝细胞癌模型中的来源及免疫调节作用。将抗IL-6和抗PD-11联合应用于荷肝癌小鼠体内。我们发现，在肝细胞癌中，IL-6主要由肿瘤相关成纤维细胞(CAF)分泌，而不是肿瘤细胞。高表达IL-6的CAF可通过募集免疫抑制细胞，如髓系抑制细胞，在肝细胞癌微环境中诱导强烈的免疫抑制。此外，高表达IL-6的CAF还通过上调抑制性免疫检查点来损害肿瘤的浸润性T细胞功能。应用IL-6阻断可逆转肝癌模型对PD-Li的耐药性。综上所述，我们的研究表明，靶向抑制IL-6可能会增强抗PD-LL在肝癌中的疗效，为克服肝癌中抗PD-LL耐药性提供了潜在的策略。(C)2017年由Elsevier Inc.发表。
Limited efficacy of immune checkpoint inhibitors in hepatocellular carcinoma (HCC) was observed in clinical trials, thus prompting investigation into combination therapy. Interleukin-6 (IL-6) has important roles in modeling immune responses in cancers. Here, we hypothesized that IL-6 blockade would enhance antitumor immunity of HCC and synergize with anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor in treating HCC. The sources and immune modulating effects of IL-6 were investigated in HCC models. Combination of anti-IL-6 and anti-PD-Ll was tested in HCC bearing mice. We found that IL-6 is mainly secreted by cancer associated fibroblast (CAFs), but not tumor cells in HCC. High IL-6 expression CAFs could induce strong immunosuppression in HCC microenvironment by recruiting immunosuppressive cells, such as myeloid derived suppressive cells. In addition, high IL-6 expression CAFs also impaired tumor infiltrating T-cell function via upregulating inhibitory immune checkpoints. Using IL-6 blockade could reverse anti-PD-LI resistance in HCC tumor model. In conclusion, our study indicates that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-Ll in HCC, providing a potential strategy to overcoming anti-PD-Ll resistance in HCC.(C) 2017 Published by Elsevier Inc.