Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng

Sun, Xin; Nagahama, Yasuharu; Singh, Shailendra Kumar et al.

Immunity, 2024, 57(6), 1360-1377.e13

Number of Access:1,329（2025-08-21 16:36 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/97231

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Title
Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng
Creator
CreatorName
Sun, Xin
CreatorName
Nagahama, Yasuharu
NRID
1000010792187 1000010792187
CreatorName
Singh, Shailendra Kumar
CreatorName
Kozakai, Yuuki
CreatorName
Nabeshima, Hiroshi
NRID
1000000752156 1000000752156
researchmap permalink
kiyoharufukushima521 kiyoharufukushima521
Scopus Author ID
57210935604 57210935604
CreatorName
Fukushima, Kiyoharu
CreatorName
Tanaka, Hiroki
NRID
1000010636830 1000010636830
researchmap permalink
daisukem daisukem
Scopus Author ID
35315737900 35315737900
CreatorName
Motooka, Daisuke
NRID
1000090814591 1000090814591
researchmap permalink
ef90814591 ef90814591
Scopus Author ID
57205560883 57205560883
CreatorName
Fukui, Eriko
CreatorName
Vivier, Eric
NRID
1000090597741 1000090597741
ORCID
0000-0002-2325-4893 0000-0002-2325-4893
researchmap permalink
diego_diez diego_diez
Scopus Author ID
34569502100 34569502100
CreatorName
Diez, Diego
NRID
1000050192919 1000050192919
researchmap permalink
read0191262 read0191262
Scopus Author ID
35396685700 35396685700
CreatorName
Akira, Shizuo
Subject
anti-tumor immunity
CXCR6-CXCL16 axis
IκBζ
NF-κB
NK cells
OCT2
Regnase-1
transcriptional complex
transcriptional regulation of Ifng
tumor microenvironment
Description
Sun X., Nagahama Y., Singh S.K., et al. Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng. Immunity 57, 1360 (2024); https://doi.org/10.1016/j.immuni.2024.05.006.
Abstract
Limited infiltration and activity of natural killer (NK) and T cells within the tumor microenvironment (TME) correlate with poor immunotherapy responses. Here, we examined the role of the endonuclease Regnase-1 on NK cell anti-tumor activity. NK cell-specific deletion of Regnase-1 (Reg1ΔNK) augmented cytolytic activity and interferon-gamma (IFN-γ) production in vitro and increased intra-tumoral accumulation of Reg1ΔNK-NK cells in vivo, reducing tumor growth dependent on IFN-γ. Transcriptional changes in Reg1ΔNK-NK cells included elevated IFN-γ expression, cytolytic effectors, and the chemokine receptor CXCR6. IFN-γ induced expression of the CXCR6 ligand CXCL16 on myeloid cells, promoting further recruitment of Reg1ΔNK-NK cells. Mechanistically, Regnase-1 deletion increased its targets, the transcriptional regulators OCT2 and IκBζ, following interleukin (IL)-12 and IL-18 stimulation, and the resulting OCT2-IκBζ-NF-κB complex induced Ifng transcription. Silencing Regnase-1 in human NK cells increased the expression of IFNG and POU2F2. Our findings highlight NK cell dysfunction in the TME and propose that targeting Regnase-1 could augment active NK cell persistence for cancer immunotherapy.
Publisher
Cell Press
Source Title
Immunity
Volume (Issue)
57(6)
Page
1360-1377.e13
Date of Issued
2024-06-11
Language
English
Handle URL
https://hdl.handle.net/11094/97231
PISSN
10747613
eISSN
10974180
Relation.isIdenticalTo
DOI (Publisher Version)
https://doi.org/10.1016/j.immuni.2024.05.006
Access Rights
open access
CopyRight
This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
oaire:version
Version of Record
Category
学術雑誌論文 Journal Article