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; Kozakai, Yuuki; Nabeshima, Hiroshi; Fukushima, Kiyoharu; Tanaka, Hiroki; Motooka, Daisuke; Fukui, Eriko; Vivier, Eric; Diez, Diego; Akira, Shizuo

doi:https://doi.org/10.1016/j.immuni.2024.05.006

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:1,495（2025-12-08 20:48 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

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	Immunity. 2024, 57(6), p. 1360-1377.e13
DC.title	Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng
DC.creator	Sun, Xin
	Nagahama, Yasuharu
	Singh, Shailendra Kumar
	Kozakai, Yuuki
	Nabeshima, Hiroshi
	Fukushima, Kiyoharu
	Tanaka, Hiroki
	Motooka, Daisuke
	Fukui, Eriko
	Vivier, Eric
	Diez, Diego
	Akira, Shizuo
DC.publisher	Cell Press
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-06-11
DC.identifier	https://doi.org/10.1016/j.immuni.2024.05.006
DC.subject	anti-tumor immunity
	CXCR6-CXCL16 axis
	IκBζ
	NF-κB
	NK cells
	OCT2
	Regnase-1
	transcriptional complex
	transcriptional regulation of Ifng
	tumor microenvironment
DC.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.
DCTERMS.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.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	97231
citation_title	Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2-dependent transcription of Ifng
citation_author	Sun, Xin
	Nagahama, Yasuharu
	Singh, Shailendra Kumar
	Kozakai, Yuuki
	Nabeshima, Hiroshi
	Fukushima, Kiyoharu
	Tanaka, Hiroki
	Motooka, Daisuke
	Fukui, Eriko
	Vivier, Eric
	Diez, Diego
	Akira, Shizuo
citation_publisher	Cell Press
citation_language	English
citation_date	2024-06-11
citation_journal_title	Immunity
citation_volume	57
citation_issue	6
citation_firstpage	1360
citation_lastpage	1377.e13
citation_doi	https://doi.org/10.1016/j.immuni.2024.05.006
citation_public_url	https://hdl.handle.net/11094/97231

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

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