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

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

Journal

Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354

Informations de publication

Date de publication:
07 2019
Historique:
received: 12 09 2018
accepted: 12 04 2019
pubmed: 5 6 2019
medline: 10 7 2019
entrez: 5 6 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41590-019-0400-7 PMID: 31160797 PMC: PMC6619502
pubmed: 31160797
doi: 10.1038/s41590-019-0400-7
pii: 10.1038/s41590-019-0400-7
pmc: PMC6619502
mid: NIHMS1527006
doi:

Substances chimiques

LINK-A long non-coding RNA, human 0
RNA, Long Noncoding 0
Receptors, G-Protein-Coupled 0
Tumor Suppressor Protein p53 0
Cyclic AMP-Dependent Protein Kinases EC 2.7.11.11

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

835-851

Subventions

Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214263
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220297
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA231011
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NIH HHS
ID : S10 OD012304
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA216426
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA186892
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218025
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218036
Pays : United States

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Auteurs

Qingsong Hu (Q)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Youqiong Ye (Y)

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.
ORCID: 0000-0001-8332-4710

Li-Chuan Chan (LC)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Yajuan Li (Y)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ke Liang (K)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Aifu Lin (A)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
College of Life Sciences, Zhejiang University, Hangzhou, China.

Sergey D Egranov (SD)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Yaohua Zhang (Y)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Weiya Xia (W)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Jing Gong (J)

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.

Yinghong Pan (Y)

Department of Biochemistry and Biology, University of Houston, Houston, TX, USA.
UPMC Genome Center, Pittsburgh, PA, USA.

Sujash S Chatterjee (SS)

Department of Biochemistry and Biology, University of Houston, Houston, TX, USA.

Jun Yao (J)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Kurt W Evans (KW)

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Tina K Nguyen (TK)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Peter K Park (PK)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Jiewei Liu (J)

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.

Cristian Coarfa (C)

Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA.

Sri Ramya Donepudi (SR)

Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA.

Vasanta Putluri (V)

Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA.

Nagireddy Putluri (N)

Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA.
Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA.

Arun Sreekumar (A)

Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA.
Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA.

Chandrashekar R Ambati (CR)

Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA.

David H Hawke (DH)

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Jeffrey R Marks (JR)

Department of Surgery, Division of Surgical Science, Duke University, School of Medicine, Durham, NC, USA.

Preethi H Gunaratne (PH)

Department of Biochemistry and Biology, University of Houston, Houston, TX, USA.
Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA.

Abigail S Caudle (AS)

Department of Breast Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Aysegul A Sahin (AA)

Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Gabriel N Hortobagyi (GN)

Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Funda Meric-Bernstam (F)

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Breast Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Lieping Chen (L)

Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
ORCID: 0000-0002-6825-3069

Dihua Yu (D)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Mien-Chie Hung (MC)

China Medical University, Taichung, Taiwan.

Michael A Curran (MA)

Department of Immunology, Division of Basic Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Leng Han (L)

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA. leng.han@uth.tmc.edu.
ORCID: 0000-0002-7380-2640

Chunru Lin (C)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. clin2@mdanderson.org.
The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. clin2@mdanderson.org.
ORCID: 0000-0002-6473-8229

Liuqing Yang (L)

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. lyang7@mdanderson.org.
The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. lyang7@mdanderson.org.
Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. lyang7@mdanderson.org.
ORCID: 0000-0002-6518-474X

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Classifications MeSH

questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Adénomes › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Eucaryotes › Animaux › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Immunité acquise › Immunité cellulaire › Présentation d'antigène › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Carcinogenèse › Transformation cellulaire néoplasique › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Cyclic Nucleotide-Regulated Protein Kinases › Cyclic AMP-Dependent Protein Kinases › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Évolution de la maladie › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Tumeurs › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Gènes tumoraux › Oncogènes › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Métabolisme › Phosphorylation › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › ARN long non codant › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs couplés aux protéines G › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Phénomènes du système immunitaire › Échappement de la tumeur à la surveillance immunitaire › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine p53 suppresseur de tumeur › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › Ubiquitination › Oncogenic lncRNA downregulates cancer cell...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Oncogenic lncRNA downregulates cancer cell...