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

Publication ,  Journal Article
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; Liu, J ...
Published in: Nat Immunol
July 2019

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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Published In

Nat Immunol

DOI

EISSN

1529-2916

Publication Date

July 2019

Volume

20

Issue

7

Start / End Page

835 / 851

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Ubiquitination
  • Tumor Suppressor Protein p53
  • Tumor Microenvironment
  • Tumor Escape
  • Receptors, G-Protein-Coupled
  • RNA, Long Noncoding
  • Phosphorylation
  • Oncogenes
  • Neoplasms
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hu, Q., Ye, Y., Chan, L.-C., Li, Y., Liang, K., Lin, A., … Yang, L. (2019). Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. Nat Immunol, 20(7), 835–851. https://doi.org/10.1038/s41590-019-0400-7
Hu, Qingsong, Youqiong Ye, Li-Chuan Chan, Yajuan Li, Ke Liang, Aifu Lin, Sergey D. Egranov, et al. “Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.Nat Immunol 20, no. 7 (July 2019): 835–51. https://doi.org/10.1038/s41590-019-0400-7.
Hu Q, Ye Y, Chan L-C, Li Y, Liang K, Lin A, et al. Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. Nat Immunol. 2019 Jul;20(7):835–51.
Hu, Qingsong, et al. “Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.Nat Immunol, vol. 20, no. 7, July 2019, pp. 835–51. Pubmed, doi:10.1038/s41590-019-0400-7.
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. Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. Nat Immunol. 2019 Jul;20(7):835–851.

Published In

Nat Immunol

DOI

EISSN

1529-2916

Publication Date

July 2019

Volume

20

Issue

7

Start / End Page

835 / 851

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Ubiquitination
  • Tumor Suppressor Protein p53
  • Tumor Microenvironment
  • Tumor Escape
  • Receptors, G-Protein-Coupled
  • RNA, Long Noncoding
  • Phosphorylation
  • Oncogenes
  • Neoplasms