Oncogenic lncRNA downregulates cancer cellantigen presentation and intrinsic tumor suppression
致癌的lncRNA下调癌细胞抗原呈递和内在肿瘤抑制
Nat Immunol. Jul;20(7):835-851. doi: 10.1038/s41590-019-0400-7. Epub Jun 3.
Hu Q, Ye Y, Chan LC, et al
How tumor cells genetically loseantigenicity and evade immune checkpoints remains largely elusive. We reportthat tissue-specific expression of the human long noncoding RNA LINK-A in mousemammary glands initiates metastatic mammary gland tumors, which phenotypicallyresemble human triple-negative breast cancer (TNBC). LINK-A expressionfacilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate andinhibitory G-protein-coupled receptor (GPCR) pathways, attenuating proteinkinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71.Consequently, LINK-A expression enhanced K48-polyubiquitination-mediateddegradation of the antigen peptide-loading complex (PLC) and intrinsic tumorsuppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCRantagonists stabilized the PLC components, Rb and p53, and sensitized mammarygland tumors to immune checkpoint blockers. Patients with programmed ccll deathprotein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels anddownregulated PLC components. Hence we demonstrate lncRNA-dependentdownregulation of antigenicity and intrinsic tumor suppression, which providesthe basis for developing combinational immunotherapy treatment regimens andearly TNBC prevention.
肿瘤细胞如何在遗传上丧失抗原性并逃避免疫检查点仍然很难解释清楚。我们报道，人类长非编码RNA LINK-A在小鼠乳腺中的组织特异性表达引起转移性乳腺肿瘤，其表型类似于人三阴性乳腺癌（TNBC）。 LINK-A表达促进三磷酸磷脂酰肌醇和抑制性G蛋白偶联受体（GPCR）途径之间的串扰，减弱蛋白激酶A介导的E3泛素连接酶TRIM71的磷酸化。因此，LINK-A表达增强了K48-多聚泛素化介导PLC、 Rb和p53的降解。用LINK-A锁定的核酸或GPCR拮抗剂治疗使PLC组分，Rb和p53稳定并且使乳腺肿瘤对免疫检查点阻断剂敏感。PD-1阻断性TNBC的患者表现出高LINK-A水平和低PLC组分的表达。因此，我们证明了lncRNA依赖的抗原性下调和内在肿瘤抑制，这为开发联合免疫治疗方案和早期TNBC预防提供了基础
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