Oxaliplatin-Resistant Hepatocellular Carcinoma Drives Immune Evasion Through PD-L1 Up-Regulation and PMN-Singular Recruitment.
Oxaliplatin-Resistant Hepatocellular Carcinoma Drives Immune Evasion Through PD-L1 Up-Regulation and PMN-Singular Recruitment.
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奥沙利铂耐药肝细胞癌通过PD-L1上调和pmn -奇异募集驱动免疫逃避
DOI：
10.1016/j.jcmgh.2022.12.002
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发表时间：
2023
影响因子：
7.2
通讯作者：
Yin, Xin
中科院分区：
文献类型：
--
作者：
Zhang, Feng;Hu, Keshu;Liu, Wenfeng;Quan, Bing;Li, Miao;Lu, Shenxin;Chen, Rongxin;Ren, Zhenggang;Yin, Xin
关键词：
以前，我们发现分化抑制剂或DNA结合1（ID 1）/Myc信号在奥沙利铂耐药肝细胞癌（HCC）中高度表达。本研究旨在研究ID 1/Myc信号传导在奥沙利铂耐药HCC中对免疫逃避的作用。建立了奥沙利铂（OXA）耐药HCC细胞系（Hepa 1-6-OXA、97 H-OXA和3B-OXA），并在体外和体内证实了其奥沙利铂耐受性。探讨ID 1/Myc和程序性死亡配体1（PD-L1）上调与多形核白细胞髓源性抑制细胞（PMN-MDSC）蓄积的关系。在体外和体内研究了ID 1/Myc信号调节PD-L1表达和PMN-MDSC蓄积的潜在机制。在奥沙利铂耐药的HCC中发现ID 1/Myc表达增加，并与PD-L1上调和PMN-MDSC蓄积相关。Myc的敲低使奥沙利铂耐药HCC细胞对奥沙利铂敏感，并导致肿瘤微环境中PMN-MDSC减少和干扰素-γ+ CD 8 + T细胞增加。聚合酶链反应阵列、酶联免疫吸附试验和MDSC Transwell迁移试验表明，奥沙利铂耐药HCC细胞通过趋化因子（C-C基序）配体5（CCL 5）招募PMN-MDSC。双荧光素酶报告基因实验和染色质免疫沉淀实验表明Myc可直接增加PD-L1和CCL 5的转录。此外，抗PD-L1抗体联合CCL 5阻断剂在奥沙利铂耐药HCC中显示出显著的抗肿瘤作用。ID 1/Myc信号通过PD-L1上调和PMN-MDSC募集驱动奥沙利铂耐药HCC的免疫逃避阻断ID 1/Myc诱导的免疫耐受代表了克服HCC化疗耐药性的有希望的治疗靶点。
Previously, we showed the inhibitor of differentiation or DNA binding 1 (ID1)/Myc signaling is highly expressed in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study sought to investigate the role of ID1/Myc signaling on immune evasion in oxaliplatin-resistant HCC. The oxaliplatin (OXA)-resistant HCC cell lines (Hepa 1-6–OXA, 97H-OXA, and 3B-OXA) were established and their oxaliplatin tolerance was confirmed in vitro and in vivo. The relationship between ID1/Myc and programmed death-ligand 1 (PD-L1) up-regulation and polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) accumulation was explored. The underlying mechanism in which ID1/Myc signaling regulated PD-L1 expression and PMN-MDSC accumulation was investigated in vitro and vivo. Increased ID1/Myc expression was identified in oxaliplatin-resistant HCC and correlated with PD-L1 up-regulation and PMN-MDSC accumulation. The knockdown of Myc sensitized oxaliplatin-resistant HCC cells to oxaliplatin and resulted in a decrease of PMN-MDSCs and an increase of interferon-γ+ CD8+ T cells in a tumor microenvironment. Polymerase chain reaction array, enzyme-linked immunosorbent assay, and MDSC Transwell migration assay indicated that oxaliplatin-resistant HCC cells recruited PMN-MDSCs through chemokine (C-C motif) ligand 5 (CCL5). The dual luciferase reporter assay and chromatin immunoprecipitation assay indicated that Myc could directly increase the transcriptions of PD-L1 and CCL5. Furthermore, anti–PD-L1 antibody combined with CCL5 blockade showed significant antitumor effects in oxaliplatin-resistant HCC. ID1/Myc signaling drives immune evasion in oxaliplatin-resistant HCC via PD-L1 up-regulation and PMN-MDSC recruitment. Blocking the ID1/Myc-induced immune tolerance represents a promising treatment target to conquer chemoresistance in HCC.
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DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
1.7
作者：
Przybyla, Tomasz;Sakowicz-Burkiewicz, Monika;Pawelczyk, Tadeusz
通讯作者：
Pawelczyk, Tadeusz
影响因子：
6.2
作者：
Matsuda, Y;Yamagiwa, S;Aoyagi, Y
通讯作者：
Aoyagi, Y
影响因子：
3.7
作者：
Bu Y;Jia QA;Ren ZG;Zhang JB;Jiang XM;Liang L;Xue TC;Zhang QB;Wang YH;Zhang L;Xie XY;Tang ZY
通讯作者：
Tang ZY
影响因子：
16.6
作者：
Bronte V;Brandau S;Chen SH;Colombo MP;Frey AB;Greten TF;Mandruzzato S;Murray PJ;Ochoa A;Ostrand-Rosenberg S;Rodriguez PC;Sica A;Umansky V;Vonderheide RH;Gabrilovich DI
通讯作者：
Gabrilovich DI