Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hu, Q; Ye, Y; Chan, L-C; Li, Y; Liang, K; Lin, A; Egranov, SD; Zhang, Y; Xia, W; Gong, J; Pan, Y; Chatterjee, SS; Yao, J; Evans, KW; Nguyen, TK; Park, PK; Liu, J; Coarfa, C; Donepudi, SR; Putluri, V; Putluri, N; Sreekumar, A; Ambati, CR; Hawke, DH; Marks, JR; Gunaratne, PH; Caudle, AS; Sahin, AA; Hortobagyi, GN; Meric-Bernstam, F; Chen, L; Yu, D; Hung, M-C; Curran, MA; Han, L; Lin, C; Yang, L

Published Date

  • July 2019

Published In

Volume / Issue

  • 20 / 7

Start / End Page

  • 835 - 851

PubMed ID

  • 31160797

Pubmed Central ID

  • 31160797

Electronic International Standard Serial Number (EISSN)

  • 1529-2916

Digital Object Identifier (DOI)

  • 10.1038/s41590-019-0400-7

Language

  • eng

Conference Location

  • United States