Long Noncoding RNAs Control the Modulation of Immune Checkpoint Molecules in Cancer
Long Noncoding RNAs Control the Modulation of Immune Checkpoint Molecules in Cancer
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DOI：
10.1158/2326-6066.cir-19-0696
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发表时间：
2020-07-01
影响因子：
10.1
通讯作者：
Pang, Da
中科院分区：
文献类型：
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作者：
Xu, Shouping;Wang, Qin;Pang, Da
与免疫检查点相关的长非编码RNA(LncRNA)尚未被识别，而且这种LncRNA调节免疫检查点表达的机制在人类癌症中也是未知的。通过对癌症基因组图谱数据的全面生物信息学分析，鉴定和验证了免疫检查点相关的lncRNA(ICP-lncRNA)。这些ICP-lncRNAs参与了关键的免疫应答和免疫细胞受体信号转导通路。在癌症患者中，ICP1ncRNAs表达上调，与预后不良相关。HL A复合体P5(HCP5)和心肌梗死相关转录本(MIAT)通过竞争的内源性RNA海绵miR-150-5p机制促进肿瘤生长和上调PD-L1/CD274的表达。MIAT基因敲除与PD-L1抗体联合应用对肿瘤生长有协同抑制作用。最后，CCCTC结合因子(CTCF)在转录水平上抑制了HCP5和MIAT的表达，脂多糖诱导CTCF从HCP5和MIAT启动子中被逐出，减弱了CTCF的转录抑制活性。这项研究扩大了人类癌症中已知的lncRNAs的功能图景，并对它们在肿瘤免疫和免疫治疗领域中的作用提出了新的见解。这些发现可能有助于免疫疗法对人类癌症的综合治疗。
Long noncoding RNAs (lncRNA) that are associated with immune checkpoints have not been identified, and the mechanism by which such lncRNAs might regulate the expression of immune checkpoints is unknown in human cancer. Immune checkpoint-associated lncRNAs (ICP-lncRNA) were identified and validated via a comprehensive bioinformatic analysis of The Cancer Genome Atlas data. These ICP-lncRNAs were involved in key immune response and immune cell receptor signaling pathways. The expression of ICP-lncRNAs was upregulated and correlated with a poor prognosis in patients with cancer. HLA complex P5 (HCP5) and myocardial infarction associated transcript (MIAT) promoted tumor growth and upregulated the expression of PD-L1/CD274 via a competing endogenous RNA mechanism of sponging miR-150-5p. The combination of MIAT knockdown and PD-L1 antibody administration showed a synergistic inhibitory effect on tumor growth. Finally, the expression of both HCP5 and MIAT was confirmed to be transcriptionally suppressed by CCCTC-binding factor (CTCF), and lipopolysaccharide induced CTCF eviction from the HCP5 and MIAT promoters, attenuating the transcriptionally suppressive activity of CTCF. This study enlarges the functional landscape of known lncRNAs in human cancer and indicates novel insights into their roles in the field of tumor immunity and immunotherapy. These findings may aid in the comprehensive management of human cancer with immunotherapy.