协同刺激分子sPD-L1在肝细胞癌动脉化疗栓塞治疗中诱发癌细胞免疫逃逸机制研究

Transcatheter hepatic arterial cheomoembolization therapy is the main effective treatment procedure of advanced hepatic carcinoma till now, unfortunately, progression often occurs which caused by the residual tumor cells and immunologic escape. Immunologic inhibitory pathway of PD-1/PD-L1 plays an important role in inducing the body immunological tolerance and the immunologic escape of tumor cells. So far we know little about the relationship between sPD-L1 and liver cancer progression after interventional therapy. The pilot experiments showed that the expression levels of sPD-L1 is closely related to the therapeutic efficacy in TACE therapy of liver cancer, and it need to be further researched. To this end, we propose the hypothesis: T cell could not remove the spreading tumor cells because of the blocking of PD-1/PD-L1. All this cause tumor progression. To test this hypothesis, we explore the mechanism of soluble PD-L1 induce cancerous cells immune escape of hepatic carcinoma in the cell, molecule and body. This study will lay the oundation for the mechanism of soluble PD-L1 induce cancerous cells immune escape of hepatic carcinoma in the TACE therapy, and provide some new ideas on improving therapeutic efficacy in TACE therapy.

动脉化疗栓塞治疗是中晚期肝癌治疗手的主要手段，但栓塞治疗后肿瘤细胞的残留和免疫逃逸是限制其疗效的关键。免疫抑制途径PD-1/PD-L1对机体免疫耐受和肿瘤细胞免疫逃逸具有重要意义。然而，迄今对sPD-L1与导致肝癌栓塞治疗后发生肿瘤进展的机制未有深入研究。我们前期实验提示sPD-L1的表达水平与肝癌动脉化疗栓塞疗效密切相关，但其作用机制有待进一步研究。为此，我们提出假说，在肝癌栓塞治疗中，由于PD-1/PD-L1的阻断作用，T细胞无法有效活化, 不能及时清除播散的肝癌细胞，导致肿瘤进展。本研究旨在通过通过ELISA、FCM等手段，从分子、细胞、动物整体水平等多方面，探讨sPD-L1在肝癌动脉栓塞治疗中诱发癌细胞免疫逃逸机制，阐述sPD-L1对T、B细胞的调控机制。本研究将从sPD-L1这个切入点揭示肝癌动脉栓塞治疗后癌细胞免疫逃逸的机制，为提高肝癌患者栓塞治疗疗效提供新思路。

免疫抑制途径PD-1/PD-L1对机肿瘤的发生、发展、转移以及肿瘤免疫逃逸具有重要意义。然而，迄今对PD-L1与导致肝癌栓塞治疗（TACE）后发生肿瘤进展的机制未有深入研究。本研究通过检测肝癌患者TACE治疗前后血液标本中sPD-L1的表达变化，并在细胞和动物水平，运用细胞转染、流式细胞术、CCK-8、Transwell、免疫组化等手段，以期明确PD-L1表达及干预在中晚期肝癌介入治疗中的作用和机制。结果发现：（1）sPD-L1的含量在HCC细胞肝癌患者外周血中明显比正常人高；（2）中晚期HCC患者TACE术后客观缓解者血清sPD-L1水平较术前显著降低；（3）在索拉菲尼耐药HCC细胞株中，PD-L1表达明显上调，并通过PI3K/Akt通路促进其EMT、迁移和侵袭；（4）hsa_circ_0003288/miR-145/PD-L1轴促进HCC细胞的EMT、迁移和侵袭；（5）在TACE联合免疫检查点抑制剂（ICIs）和酪氨酸激酶抑制剂（TKIs）的研究方面开展了一系列探索，并且进行了一项单中心研究，发现TACE联合Lenvatinib和Camrelizumab的治疗显示可以接受的副作用并且疗效好，从而从不同角度验证了TACE联合TKIs与ICIs的可行性（6）Lenvatinib能抑制PD-L1的表达，并且PD-L1能够调节HUVEC的血管生成。由以上结果得出结论，PD-L1有望成为HCC的基因治疗靶标并作为TACE治疗的生物标志物。