长非编码 RNA 控制癌症中免疫检查点分子的调节。

Long Noncoding RNAs Control the Modulation of Immune Checkpoint Molecules in Cancer.

机构信息

Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.

Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang, China.

出版信息

Cancer Immunol Res. 2020 Jul;8(7):937-951. doi: 10.1158/2326-6066.CIR-19-0696. Epub 2020 Apr 22.

Abstract

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.

摘要

长链非编码 RNA(lncRNA)与免疫检查点相关,但尚未被鉴定,并且这些 lncRNA 可能调节免疫检查点表达的机制在人类癌症中尚不清楚。通过对癌症基因组图谱数据进行全面的生物信息学分析,鉴定并验证了与免疫检查点相关的 lncRNA(ICP-lncRNA)。这些 ICP-lncRNA 参与了关键的免疫反应和免疫细胞受体信号通路。ICP-lncRNA 的表达上调与癌症患者的预后不良相关。HLA 复合体 P5(HCP5)和心肌梗塞相关转录物(MIAT)通过竞争性内源性 RNA 机制海绵 miR-150-5p 促进肿瘤生长并上调 PD-L1/CD274 的表达。MIAT 敲低和 PD-L1 抗体给药的联合使用对肿瘤生长表现出协同抑制作用。最后,证实 HCP5 和 MIAT 的表达均受结合因子(CTCF)的转录抑制,脂多糖诱导 CTCF 从 HCP5 和 MIAT 启动子中迁出,从而减弱 CTCF 的转录抑制活性。这项研究扩大了已知 lncRNA 在人类癌症中的功能范围,并为它们在肿瘤免疫和免疫治疗领域的作用提供了新的见解。这些发现可能有助于免疫疗法全面管理人类癌症。

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