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Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression
Open accessAbstract
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. Many tumors evade immunosurveillance by down-modulating expression of antigen-processing machinery and MHC molecules. Yang et al. report triple-negative tumor cell expression of the lncRNA LINK-A enhances degradation of antigen peptide-loading complex molecules and intrinsic tumor suppressors, which contribute to tumor persistence.
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Metadata
- Authors
- Hu, Q., Ye, Y., Chan, L.-C., Li, Y., Liang, K., Lin, A., Egranov, S. D., Zhang, Y., Xia, W., Gong, J., Pan, Y., Chatterjee, S. S., Yao, J., Evans, K. W., Nguyen, T. K., Park, P. K., Liu, J., Coarfa, C., Donepudi, S. R., Putluri, V., Putluri, N., Sreekumar, A., Ambati, C. R., Hawke, D. H., Marks, J. R., Gunaratne, P. H., Caudle, A. S., Sahin, A. A., Hortobagyi, G. N., Meric-Bernstam, F., Chen, L., Yu, D., Hung, M.-C., Curran, M. A., Han, L., Lin, C., & Yang, L.
- Venue
- Nature Immunology
- Published
- 2019-06-03
- Volume
- 20
- Issue
- 7
- Pages
- 835-851
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2947420752
- Cited by
- 353
- References
- 60
- FWCI
- 18.41
- Type
- journal article
- Language
- en
- Open access
- green
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- Hu, Q., Ye, Y., Chan, L.-C., Li, Y., Liang, K., Lin, A., Egranov, S. D., Zhang, Y., Xia, W., Gong, J., Pan, Y., Chatterjee, S. S., Yao, J., Evans, K. W., Nguyen, T. K., Park, P. K., Liu, J., Coarfa, C., Donepudi, S. R., . . . Yang, L. (2019). Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. Nature Immunology. https://doi.org/10.1038/s41590-019-0400-7
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