@article{6c53619bc2c140a9b9b3e07ddbc5e2dc,
title = "Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression",
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.",
author = "Qingsong Hu and Youqiong Ye and Chan, {Li Chuan} and Yajuan Li and Ke Liang and Aifu Lin and Egranov, {Sergey D.} and Yaohua Zhang and Weiya Xia and Jing Gong and Yinghong Pan and Chatterjee, {Sujash S.} and Jun Yao and Evans, {Kurt W.} and Nguyen, {Tina K.} and Park, {Peter K.} and Jiewei Liu and Cristian Coarfa and Donepudi, {Sri Ramya} and Vasanta Putluri and Nagireddy Putluri and Arun Sreekumar and Ambati, {Chandrashekar R.} and Hawke, {David H.} and Marks, {Jeffrey R.} and Gunaratne, {Preethi H.} and Caudle, {Abigail S.} and Sahin, {Aysegul A.} and Hortobagyi, {Gabriel N.} and Funda Meric-Bernstam and Lieping Chen and Dihua Yu and Hung, {Mien Chie} and Curran, {Michael A.} and Leng Han and Chunru Lin and Liuqing Yang",
note = "Funding Information: The Proteomics and Metabolomics Facility was supported in part by a Cancer Prevention Research Institute of Texas (CPRIT) grant (no. RP130397) and a National Institutes of Health (NIH) grant (no. 1S10OD012304-01 to D.H.H.). This project is partially supported by University of Houston (UH) Seq-N-Edit Core with funding from UH Division of Research; UH College of NSM and Department of Biology & Biochemistry; NRUF MINOR CORE 17 Grant (to P.H.G.) and UH Small Core Equipment Program Grant (to P.H.G.). We thank the core facilities at BCM: Metabolomics Core (NIH grant no. P30CA125123), CPRIT Proteomics and Metabolomics Core Facility (grant no. RP170005 to N.P.) and Dan L. Duncan Cancer Center. This work was supported by grant nos. R01CA216426, R01CA220297 and U01CA214263 from NIH and 127430-RSG-15-105-01-CNE from the American Cancer Society (to N.P.). This project was partially supported by the NIH T32 Training Grant in Cancer Biology (grant no. 5T32CA186892 to L.-C.C.). This project was also supported by Cancer Prevention & Research Institute of Texas grant (no. RR150085 to L.H.). This work was supported by NIH R01 awards (nos. 1R01CA218025-01 and 1R01CA231011-01), CPRIT individual investigator research award (nos. RP150094 and RP180259) and Department of Defense Breakthrough award (no. BC180196 to C.L.). This work was supported by an NIH R01 award (no. 1R01CA218036-01), CPRIT First-time Faculty Recruitment Award (no. R1218), Department of Defense Breakthrough award (no. BC151465), The American Association for Cancer Research-Bayer Innovation and Discovery Grant (no. 18-80-44) and Andrew Sabin Family Foundation Fellows Award (to L.Y.). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = jul,
day = "1",
doi = "10.1038/s41590-019-0400-7",
language = "English (US)",
volume = "20",
pages = "835--851",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "7",
}