德克萨斯大学安德森癌症中心Liuqing Yang研究小组近日取得一项新成果。他们探明了致癌性lncRNA下调癌细胞抗原表达和肿瘤内在抑制。 这一研究成果发表在2019年7月出版的国际学术期刊《自然—免疫学》上。

研究报道了在小鼠乳腺中的组织特异性表达人类长链非编码RNA-A引发转移性乳腺肿瘤，其表型类似于人类三阴性乳腺癌(TNBC)。LINK-A的表达促进了磷脂酰肌醇-(3,4,5)-三磷酸与抑制G蛋白偶联受体(GPCR)通路之间的相互作用，减弱了蛋白激酶A介导的E3泛素连接酶TRIM71磷酸化。因此，LINK-A表达增强了K48 -多聚泛素化介导的抗原多肽复合物(PLC)和肿瘤内在抑制因子Rb和p53的降解。使用LINK-A阻断剂或GPCR拮抗剂治疗可稳定PLC成分、Rb和p53，并使乳腺肿瘤对免疫检查点阻滞剂敏感。程序性细胞死亡蛋白-1(PD-1)耐阻断TNBC患者的LINK-A水平升高，PLC元件下调。因此，研究证明了 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。

研究人员表示，肿瘤细胞在基因上是如何失去抗原性并逃避免疫检查点的，在很大程度上仍是个谜。

附：英文原文

Title: Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression

Author: Qingsong Hu, Youqiong Ye, Li-Chuan Chan, Yajuan Li, Ke Liang, Aifu Lin, Sergey D. Egranov, Yaohua Zhang, Weiya Xia, Jing Gong, Yinghong Pan, Sujash S. Chatterjee, Jun Yao, Kurt W. Evans, Tina K. Nguyen, Peter K. Park, Jiewei Liu, Cristian Coarfa, Sri Ramya Donepudi, Vasanta Putluri, Nagireddy Putluri, Arun Sreekumar, Chandrashekar R. Ambati, David H. Hawke, Jeffrey R. Marks, Preethi H. Gunaratne, Abigail S. Caudle, Aysegul A. Sahin, Gabriel N. Hortobagyi, Funda Meric-Bernstam, Lieping Chen, Dihua Yu, Mien-Chie Hung, Michael A. Curran, Leng Han, Chunru Lin, Liuqing Yang

Issue&Volume: Volume 20 Issue 7, July 2019

Abstract: How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

DOI: 10.1038/s41590-019-0400-7

Source:https://www.nature.com/articles/s41590-019-0400-7