The Oncometabolite 5'-Deoxy-5'-Methylthioadenosine Blocks Multiple Signaling Pathways of NK Cell Activation.
CD57 Antigens
/ immunology
Cell Degranulation
/ drug effects
Cells, Cultured
Cytokines
/ biosynthesis
Cytotoxicity, Immunologic
Deoxyadenosines
/ pharmacology
GPI-Linked Proteins
/ physiology
Humans
Immunosuppression Therapy
Interferon-gamma
/ biosynthesis
K562 Cells
Killer Cells, Natural
/ drug effects
Lymphocyte Subsets
/ drug effects
Lysosomal-Associated Membrane Protein 1
/ biosynthesis
NF-kappa B
/ antagonists & inhibitors
NK Cell Lectin-Like Receptor Subfamily C
/ analysis
Protein-Arginine N-Methyltransferases
/ antagonists & inhibitors
Purine-Nucleoside Phosphorylase
/ metabolism
Receptors, IgG
/ physiology
Signal Transduction
/ drug effects
Thionucleosides
/ pharmacology
Tumor Escape
Tumor Stem Cell Assay
5′-deoxy-5′-methylthioadenosine
CD16 signaling
NK cells
NKG2C
tumor escape mechanism
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2020
2020
Historique:
received:
24
02
2020
accepted:
05
08
2020
entrez:
30
10
2020
pubmed:
31
10
2020
medline:
7
5
2021
Statut:
epublish
Résumé
Tumor cells develop various mechanisms to escape immune surveillance. In this context, oncometabolites secreted by tumor cells due to deregulated metabolic pathways, have been in the spotlight of researchers during the last years. 5'-Deoxy-5'-methylthioadenosine (MTA) phosphorylase (MTAP) deficiency in tumors results in the accumulation of MTA within the tumor microenvironment and thereby negatively influencing immune functions of various immune cells, including T and NK cells. The influence of MTA on T cell activation has been recently described in more detail, while its impact on NK cells is still largely unknown. Therefore, we aimed to illuminate the molecular mechanism of MTA-induced NK cell dysfunction. NK cell cytotoxicity against target cells was reduced in the presence of MTA in a dose-dependent manner, while NK cell viability remained unaffected. Furthermore, we revealed that MTA blocks NK cell degranulation and cytokine production upon target cell engagement as well as upon antibody stimulation. Interestingly, the immune-suppressive effect of MTA was less pronounced in healthy donors harboring an expansion of NKG2C
Identifiants
pubmed: 33123121
doi: 10.3389/fimmu.2020.02128
pmc: PMC7573074
doi:
Substances chimiques
CD57 Antigens
0
Cytokines
0
Deoxyadenosines
0
FCGR3B protein, human
0
GPI-Linked Proteins
0
KLRC2 protein, human
0
Lysosomal-Associated Membrane Protein 1
0
NF-kappa B
0
NK Cell Lectin-Like Receptor Subfamily C
0
Receptors, IgG
0
Thionucleosides
0
5'-methylthioadenosine
634Z2VK3UQ
Interferon-gamma
82115-62-6
PRMT5 protein, human
EC 2.1.1.319
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
Purine-Nucleoside Phosphorylase
EC 2.4.2.1
5'-methylthioadenosine phosphorylase
EC 2.4.2.28
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2128Informations de copyright
Copyright © 2020 Jacobs, Schlögl, Strobl, Völkl, Stoll, Mougiakakos, Malmberg, Mackensen and Aigner.
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