Anterior gradient 2-derived peptide upregulates major histocompatibility complex class I-related chains A/B in hepatocellular carcinoma cells
Anterior gradient 2-derived peptide upregulates major histocompatibility complex class I-related chains A/B in hepatocellular carcinoma cells
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DOI：
10.1016/j.lfs.2020.117396
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发表时间：
2020-04-01
期刊：
影响因子：
6.1
通讯作者：
Wei, Minjie
中科院分区：
文献类型：
--
作者：
Bian, Jing;He, Linxiu;Wei, Minjie
目的：肝细胞癌（HCC）是全球癌症死亡的主要原因。HCC患者中NKG 2D配体水平降低和NK细胞耗竭是免疫逃逸、高复发、预后差和总生存率低的主要原因。通过上调肿瘤细胞上的NKG 2DLs来增强HCC对NK细胞的易感性是一种有效的治疗策略。本研究的目的是鉴定前梯度2（AGR 2）衍生肽P1（据报道其结合HLA-A*0201作为表位）对HCC细胞上的主要组织相容性复合物I类相关链A/B（云母/B）的表达和NK细胞的细胞毒性的影响。通过qRT-PCR、蛋白质印迹和流式细胞术分析来确定P1对HCC细胞上的云母/B表达的影响。用各种途径抑制剂预处理HCC细胞以鉴定与P1处理相关的分子途径。LDH法检测NK细胞对肝癌细胞的杀伤活性。使用NOD/SCID小鼠HCC模型在体内测定P1的肿瘤抑制作用。关键发现：P1显著增加HCC细胞上MICAS的表达，从而增强它们对NK细胞体外和体内细胞毒性的敏感性。此外，p38 MAPK细胞信号通路抑制剂SB 203580在体内和体外显著减弱P1的作用。意义：P1上调HCC细胞上云母和MICB的表达，从而促进它们被NK细胞识别和清除，这使得P1成为一种有吸引力的新型免疫治疗剂。
Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Decrease in NKG2D ligand levels and exhaustion of NK cells in HCC patients are major causes of immune escape, high recurrence, poor prognosis, and low overall survival. Enhancing the susceptibility of HCC to NK cells by upregulating NKG2DLs on tumor cells is an effective treatment strategy. This study aimed to identify the effect of the Anterior gradient 2 (AGR2)-derived peptide P1, which was reported to bind to HLA-A*0201 as an epitope, on both the expression of major histocompatibility complex class I-related chains A/B (MICA/B) on HCC cells and the cytotoxicity of NK cells.Main methods: The effect of P1 on MICA/B expression on HCC cells was determined by qRT-PCR, western blotting, and flow cytometry analysis. HCC cells were pre-treated with various pathway inhibitors to identify the molecular pathways associated with P1 treatment. The cytotoxicity of NK cells toward HCC was investigated by LDH cytotoxicity assay. The tumor-suppression effect of P1 was determined in vivo using a NOD/SCID mice HCC model.Key findings: P1 significantly increased MICAS expression on HCC cells, thereby enhancing their susceptibility to the cytotoxicity of NK cells in vitro and in vivo. Further, p38 MAPK cell signaling pathway inhibitor SB203580 significantly attenuated the effects of P1 in vivo and in vitro.Significance: P1 upregulates MICA and MICB expression on HCC cells, thereby promoting their recognition and elimination by NK cells, which makes P1 an attractive novel immunotherapy agent.