Immunomodulatory drugs activate NK cells via both Zap-70 and cereblon-dependent pathways.
Adaptor Proteins, Signal Transducing
/ metabolism
Cell Line, Tumor
Cells, Cultured
Cytotoxicity, Immunologic
Humans
Immunologic Factors
/ pharmacology
Immunomodulation
/ drug effects
Killer Cells, Natural
/ drug effects
Lymphocyte Activation
/ drug effects
Phosphorylation
Signal Transduction
/ drug effects
T-Lymphocyte Subsets
/ immunology
Ubiquitin-Protein Ligases
/ metabolism
ZAP-70 Protein-Tyrosine Kinase
/ metabolism
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
05
11
2019
accepted:
18
03
2020
revised:
17
03
2020
pubmed:
3
4
2020
medline:
14
1
2021
entrez:
3
4
2020
Statut:
ppublish
Résumé
Immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide show remarkable antitumor activity in multiple myeloma (MM) via directly inhibiting MM-cell growth in the bone marrow (BM) microenvironment and promoting immune effector cell function. They are known to bind to the ubiquitin 3 ligase CRBN complex and thereby triggering degradation of IKZF1/3. In this study, we demonstrate that IMiDs also directly bind and activate zeta-chain-associated protein kinase-70 (Zap-70) via its tyrosine residue phosphorylation in T cells. IMiDs also triggered phosphorylation of Zap-70 in natural killer (NK) cells. Importantly, increased granzyme-B (GZM-B) expression and NK-cell activity triggered by IMiDs is associated with Zap-70 activation and inhibited by Zap-70 knockdown (KD), independent of CRBN. We also demonstrate a second mechanism whereby IMiDs trigger GZM-B and NK cytotoxicity which is CRBN and IKZF3 mediated, and inhibited or enhanced by KD of CRBN or IKZF3, respectively, independent of Zap-70. Our studies therefore show that IMiDs can enhance NK and T-cell cytotoxicity in (1) ZAP-70-mediated CRBN independent, as well as (2) CRBN-mediated ZAP-70 independent mechanisms; and provide the framework for developing novel therapeutics to activate Zap-70 and thereby enhance T and NK anti-MM cytotoxicity.
Identifiants
pubmed: 32238854
doi: 10.1038/s41375-020-0809-x
pii: 10.1038/s41375-020-0809-x
pmc: PMC7529681
mid: NIHMS1578112
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CRBN protein, human
0
Immunologic Factors
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
ZAP-70 Protein-Tyrosine Kinase
EC 2.7.10.2
ZAP70 protein, human
EC 2.7.10.2
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
177-188Subventions
Organisme : NCI NIH HHS
ID : P01 CA155258
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA050947
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178264
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA100707
Pays : United States
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