Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
22 07 2021
22 07 2021
Historique:
received:
19
12
2020
accepted:
05
07
2021
entrez:
23
7
2021
pubmed:
24
7
2021
medline:
12
11
2021
Statut:
epublish
Résumé
Natural Killer (NK) cell dysfunction is associated with poorer clinical outcome in cancer patients. What regulates NK cell dysfunction in tumor microenvironment is not well understood. Here, we demonstrate that the human tumor-derived NKG2D ligand soluble MIC (sMIC) reprograms NK cell to secrete pro-tumorigenic cytokines with diminished cytotoxicity and polyfunctional potential. Antibody clearing sMIC restores NK cell to a normal cytotoxic effector functional state. We discovered that sMIC selectively activates the CBM-signalosome inflammatory pathways in NK cells. Conversely, tumor cell membrane-bound MIC (mMIC) stimulates NK cell cytotoxicity through activating PLC2γ2/SLP-76/Vav1 pathway. Ultimately, antibody targeting sMIC effectuated the in vivo anti-tumor effect of adoptively transferred NK cells. Our findings uncover an unrecognized mechanism that could instruct NK cell to a dysfunctional state in response to cues in the tumor microenvironment. Our findings provide a rationale for co-targeting sMIC to enhance the efficacy of the ongoing NK cell-based cancer immunotherapy.
Identifiants
pubmed: 34294876
doi: 10.1038/s42003-021-02440-3
pii: 10.1038/s42003-021-02440-3
pmc: PMC8298432
doi:
Substances chimiques
KLRK1 protein, human
0
Ligands
0
NK Cell Lectin-Like Receptor Subfamily K
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
905Subventions
Organisme : NCI NIH HHS
ID : R01 CA212409
Pays : United States
Organisme : NINDS NIH HHS
ID : F32 NS073366
Pays : United States
Organisme : NINDS NIH HHS
ID : R00 NS082381
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204021
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM138192
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA207865
Pays : United States
Organisme : NIA NIH HHS
ID : K02 AG068617
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208246
Pays : United States
Organisme : NINDS NIH HHS
ID : K99 NS082381
Pays : United States
Informations de copyright
© 2021. The Author(s).
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