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.

• Authors: 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
• Journal: Nature immunology (Nat Immunol) Vol. 20 Issue 7 Pg. 835-851 (07 2019) ISSN: 1529-2916 [Electronic] United States
• PMID: 31160797 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• LINK-A long non-coding RNA, human
• RNA, Long Noncoding
• Receptors, G-Protein-Coupled
• Tumor Suppressor Protein p53
• Cyclic AMP-Dependent Protein Kinases

Topics

• Adenoma (genetics, metabolism)
• Animals
• Antigen Presentation (immunology)
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics, metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Disease Models, Animal
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Neoplasms (genetics, immunology, metabolism, pathology)
• Oncogenes
• Phosphorylation
• RNA, Long Noncoding (genetics)
• Receptors, G-Protein-Coupled (antagonists & inhibitors)
• Tumor Escape (genetics, immunology)
• Tumor Microenvironment (genetics, immunology)
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitination
• Xenograft Model Antitumor Assays