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