Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression

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 PutluriNagireddy 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)835-851
Number of pages17
JournalNature Immunology
Volume20
Issue number7
DOIs
StatePublished - Jul 1 2019

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Long Noncoding RNA
Triple Negative Breast Neoplasms
Antigen Presentation
Human Mammary Glands
Down-Regulation
G-Protein-Coupled Receptors
Peptides
Breast Neoplasms
Neoplasms
Ubiquitin-Protein Ligases
Cyclic AMP-Dependent Protein Kinases
Immunotherapy
Phosphorylation
Antigens
Therapeutics
Proteins

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. / Hu, Qingsong; Ye, Youqiong; Chan, Li Chuan; Li, Yajuan; Liang, Ke; Lin, Aifu; Egranov, Sergey D.; Zhang, Yaohua; Xia, Weiya; Gong, Jing; Pan, Yinghong; Chatterjee, Sujash S.; Yao, Jun; Evans, Kurt W.; Nguyen, Tina K.; Park, Peter K.; Liu, Jiewei; Coarfa, Cristian; Donepudi, Sri Ramya; Putluri, Vasanta; Putluri, Nagireddy; Sreekumar, Arun; Ambati, Chandrashekar R.; Hawke, David H.; Marks, Jeffrey R.; Gunaratne, Preethi H.; Caudle, Abigail S.; Sahin, Aysegul A.; Hortobagyi, Gabriel N.; Meric-Bernstam, Funda; Chen, Lieping; Yu, Dihua; Hung, Mien Chie; Curran, Michael A.; Han, Leng; Lin, Chunru; Yang, Liuqing.

In: Nature Immunology, Vol. 20, No. 7, 01.07.2019, p. 835-851.

Research output: Contribution to journalArticle

Hu, Q, Ye, Y, Chan, LC, 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, MC, Curran, MA, Han, L, Lin, C & Yang, L 2019, 'Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression', Nature Immunology, vol. 20, no. 7, pp. 835-851. https://doi.org/10.1038/s41590-019-0400-7
Hu, Qingsong ; Ye, Youqiong ; Chan, Li Chuan ; Li, Yajuan ; Liang, Ke ; Lin, Aifu ; Egranov, Sergey D. ; Zhang, Yaohua ; Xia, Weiya ; Gong, Jing ; Pan, Yinghong ; Chatterjee, Sujash S. ; Yao, Jun ; Evans, Kurt W. ; Nguyen, Tina K. ; Park, Peter K. ; Liu, Jiewei ; Coarfa, Cristian ; Donepudi, Sri Ramya ; Putluri, Vasanta ; Putluri, Nagireddy ; Sreekumar, Arun ; Ambati, Chandrashekar R. ; Hawke, David H. ; Marks, Jeffrey R. ; Gunaratne, Preethi H. ; Caudle, Abigail S. ; Sahin, Aysegul A. ; Hortobagyi, Gabriel N. ; Meric-Bernstam, Funda ; Chen, Lieping ; Yu, Dihua ; Hung, Mien Chie ; Curran, Michael A. ; Han, Leng ; Lin, Chunru ; Yang, Liuqing. / Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. In: Nature Immunology. 2019 ; Vol. 20, No. 7. pp. 835-851.
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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.",
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T1 - Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression

AU - Hu, Qingsong

AU - Ye, Youqiong

AU - Chan, Li Chuan

AU - Li, Yajuan

AU - Liang, Ke

AU - Lin, Aifu

AU - Egranov, Sergey D.

AU - Zhang, Yaohua

AU - Xia, Weiya

AU - Gong, Jing

AU - Pan, Yinghong

AU - Chatterjee, Sujash S.

AU - Yao, Jun

AU - Evans, Kurt W.

AU - Nguyen, Tina K.

AU - Park, Peter K.

AU - Liu, Jiewei

AU - Coarfa, Cristian

AU - Donepudi, Sri Ramya

AU - Putluri, Vasanta

AU - Putluri, Nagireddy

AU - Sreekumar, Arun

AU - Ambati, Chandrashekar R.

AU - Hawke, David H.

AU - Marks, Jeffrey R.

AU - Gunaratne, Preethi H.

AU - Caudle, Abigail S.

AU - Sahin, Aysegul A.

AU - Hortobagyi, Gabriel N.

AU - Meric-Bernstam, Funda

AU - Chen, Lieping

AU - Yu, Dihua

AU - Hung, Mien Chie

AU - Curran, Michael A.

AU - Han, Leng

AU - Lin, Chunru

AU - Yang, Liuqing

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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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