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The let-7 family of microRNAs suppresses immune evasion in head and neck squamous cell carcinoma by promoting PD-L1 degradation.
Cell Communication and Signaling ( IF 8.4 ) Pub Date : 2019-12-27 , DOI: 10.1186/s12964-019-0490-8
Dan Yu 1 , Xueshibojie Liu 1 , Guanghong Han 2 , Yan Liu 1 , Xue Zhao 1 , Di Wang 1 , Xiaomin Bian 1 , Tingting Gu 1 , Lianji Wen 1
Affiliation  

BACKGROUND Accumulation of immunosuppressive protein programmed death-ligand 1 (PD-L1) has been documented in several cancers and contributes to the evasion of the host immune system. However, cancer cell-intrinsic signaling-dependent control of PD-L1 expression remains to be elucidated. Herein, we aimed to identify the let-7 family of microRNAs as candidates that up-regulate tumor cell PD-L1 expression and mediates immune evasion of head and neck squamous cell carcinoma (HNSCC). METHODS The expression of let-7 family and PD-L1 was quantified in HNSCC tissues and adjacent normal tissues. PD-L1 degradation was evaluated in HNSCC cells in response to elevated expressions of let-7a or let-7b. The regulation of let-7 family on PD-L1 degradation through a mechanism involving T-cell factor-4 (TCF-4) control of β-catenin/STT3 pathway was evaluated. Immune recognition of HNSCC in vivo was examined in subcutaneous tumor-bearing C3H mice in the presence of let-7a/b and/or CTLA-4 antibody. RESULTS The let-7 family were significantly down-regulated in the context of HNSCC, sharing a negative correlation with PD-L1 expression. Glycosylated PD-L1 was detected in HNSCC cells, which was reduced by let-7a/b over-expression. TCF-4, the target of let-7a/b, activated the β-catenin/STT3 pathway and promoted PD-L1 degradation. In vivo analysis demonstrated that let-7a/b over-expression potentiated anticancer immunotherapy by CTLA-4 blockade. CONCLUSIONS Taken together, our findings highlight targeting let-7 family as a potential strategy to enhance immune checkpoint therapy for HNSCC.

中文翻译:

let-7家族的microRNA通过促进PD-L1降解来抑制头颈部鳞状细胞癌的免疫逃逸。

背景技术已经在几种癌症中记录了免疫抑制蛋白程序性死亡配体1(PD-L1)的积累,并有助于逃避宿主免疫系统。然而,仍然需要阐明癌细胞内在信号传导依赖性的PD-L1表达控制。在这里,我们旨在确定let-7家族的microRNA作为候选蛋白,上调肿瘤细胞PD-L1的表达并介导头颈部鳞状细胞癌(HNSCC)的免疫逃逸。方法定量检测HNSCC组织和邻近正常组织中let-7家族和PD-L1的表达。响应let-7a或let-7b表达升高,在HNSCC细胞中评估PD-L1降解。评价了let-7家族通过涉及T细胞因子4(TCF-4)控制β-catenin/ STT3途径的机制对PD-L1降解的调控。在let-7a / b和/或CTLA-4抗体存在的情况下,在具有皮下肿瘤的C3H小鼠中检查了体内对HNSCC的免疫识别。结果在HNSCC的情况下,let-7家族被显着下调,与PD-L1表达负相关。在HNSCC细胞中检测到糖基化的PD-L1,其被let-7a / b过表达减少。let-7a / b的靶标TCF-4激活了β-catenin/ STT3途径并促进了PD-L1的降解。体内分析表明,leta-7a / b过表达可通过CTLA-4阻断增强抗癌免疫疗法。结论综上所述,我们的研究结果突出了针对let-7家族作为增强HNSCC免疫检查点治疗的潜在策略。
更新日期:2019-12-30
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