miR-105-5p regulates PD-L1 expression and tumor immunogenicity in gastric cancer.
miR-105-5p regulates PD-L1 expression and tumor immunogenicity in gastric cancer.
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DOI：
10.1016/j.canlet.2021.05.037
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发表时间：
2021-10-10
期刊：
影响因子：
9.7
通讯作者：
Slack FJ
中科院分区：
文献类型：
--
作者：
Miliotis C;Slack FJ
靶向程序性死亡1（PD-1）和程序性死亡配体1（PD-L1）之间相互作用的癌症免疫疗法最近已被批准用于治疗多种癌症类型，包括胃癌。然而，并非所有患者都对这些疗法有反应，有些患者最终会产生耐药性。对PD-1/PD-L1治疗的阳性应答的部分预测生物标志物是PD-L1表达，其已被证明在癌症中处于严格的转录后控制下。通过将PD-L1 3′非翻译区（3′UTR）分离成多个重叠片段，我们确定了一个小的100个核苷酸长的顺式作用区，该区域是胃癌中PD-L1表达的转录后抑制所必需和充分的。同时，我们在胃癌患者样本中进行了PD-L1表达与所有宿主miRNA之间的相关性分析。预测单个miRNA miR-105- 5 p与已鉴定的顺式作用3′UTR区域结合，并与PD-L1表达呈负相关。胃癌细胞系中miR-105- 5 p的过表达导致PD-L1在总蛋白和表面表达水平上的表达降低，并在共培养试验中诱导CD 8 + T细胞活化。最后，我们发现miR-105- 5 p在胃癌中的表达部分受其宿主基因GABRA 3的癌症和种系特异性启动子的DNA甲基化控制。在许多癌症类型中观察到miR-105- 5 p的失调，这项研究显示了这种miRNA在控制癌细胞免疫原性方面的重要性，从而突出了它作为PD-1/PD-L1治疗的潜在生物标志物和组合免疫治疗的靶标。
Cancer immunotherapies targeting the interaction between Programmed death 1 (PD-1) and Programmed death ligand 1 (PD-L1) have recently been approved for the treatment of multiple cancer types, including gastric cancer. However, not all patients respond to these therapies, while some eventually acquire resistance. A partial predictive biomarker for positive response to PD-1/PD-L1 therapy is PD-L1 expression, which has been shown to be under strict post-transcriptional control in cancer. By fractionating the PD-L1 3′ untranslated region (3′UTR) into multiple overlapping fragments, we identified a small 100-nucleotide-long cis-acting region as being necessary and sufficient for post-transcriptional repression of PD-L1 expression in gastric cancer. In parallel, we performed a correlation analysis between PD-L1 expression and all host miRNAs in stomach cancer patient samples. A single miRNA, miR-105-5p, was predicted to bind to the identified cis-acting 3′UTR region and to negatively correlate with PD-L1 expression. Overexpression of miR-105-5p in gastric cancer cell lines resulted in decreased expression of PD-L1, both at the total protein and surface expression levels, and induced CD8+ T cell activation in co-culture assays. Finally, we show that expression of miR-105-5p in gastric cancer is partly controlled by DNA methylation of a cancer- and germline-specific promoter of its host gene, GABRA3. Dysregulation of miR-105-5p is observed in many cancer types and this study shows the importance of this miRNA in controlling the immunogenicity of cancer cells, thus highlighting it as a potential biomarker for PD-1/PD-L1 therapy and target for combinatorial immunotherapy.
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