Journal
NATURE IMMUNOLOGY
Volume 20, Issue 7, Pages 835-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-019-0400-7
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Funding
- Cancer Prevention Research Institute of Texas (CPRIT) [RP130397]
- National Institutes of Health (NIH) grant [1S10OD012304-01]
- University of Houston
- UH Division of Research
- UH College of NSM
- UH Small Core Equipment Program [P30CA125123]
- CPRIT Proteomics and Metabolomics Core Facility [RP170005]
- Dan L. Duncan Cancer Center [R01CA216426, R01CA220297, U01CA214263]
- NIH [127430-RSG-15-105-01-CNE]
- American Cancer Society
- NIH T32 Training Grant in Cancer Biology [5T32CA186892]
- Cancer Prevention & Research Institute of Texas grant [RR150085]
- NIH R01 awards [1R01CA218025-01, 1R01CA231011-01]
- CPRIT individual investigator research award [RP150094, RP180259]
- Department of Defense Breakthrough award [BC151465]
- NIH R01 award [1R01CA218036-01]
- CPRIT First-time Faculty Recruitment Award [R1218]
- American Association for Cancer Research-Bayer Innovation and Discovery Grant [18-80-44]
- Andrew Sabin Family Foundation Fellows Award
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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.
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