Pulling out the stops: Deletion of regnase-1 promotes anti-tumor activity
in NK cells
Osaka, Japan - Natural killer (NK) cells play a crucial role in the first line of hostdefense by eliminating bacteria, viruses, and mutated cells that might becomecancer cells. While the interferon-gamma (IFN-γ) typically plays a pivotal role in
the function of NK cells, the detailed mechanisms of its regulation have notbeen fully elucidated. In clinical cancer treatment, particularly in anti-tumor
immunotherapy, the challenge lies in regulating the effective infiltration of NK
cells and T cells into tumor tissues, activating them, and retaining them within
the tumor for more effective cancer therapy.
Performing single-cell RNA sequencing (scRNA-seq) analysis of tumor cells
from wild-type mice and NK cell-specific Regnase-1 deficient mice, a researchcollaboration led by Xin Sun, Diego Diez, and Shizuo Akira at the Immunology
Frontier Research Center (IFReC) of Osaka University and Yasuharu
Nagahama at the Osaka Research Center for Drug Discovery of Otsuka
Pharmaceutical Co., Ltd. has revealed that deletion of mRNA endonucleaseRegnase-1 promoted NK cell anti-tumor activity via OCT2-dependenttranscriptional up-regulation of Ifng mRNA. Their findings are illustrated inFigure 1.

Fig. 1
Regnase-1 deficient NK cells highly
express Ifng depend on thecooperation of OCT2, IκBζ, and NFκB transcriptional complex. Thistranscriptional upregulation of Ifng
induced the high IFN-γ production
from NK cells, leading to thealteration of tumor microenvironmentthat support the activation andpersistence of NK cells inside thetumor microenvironment.
Yasuharu Nagahama (Created withBioRender.com)

Dr. Nagahama, a lead co-author of the study, explained, “Our investigation
showed the contribution of B cell-specific OCT2 transcription factor for NK cellbiology, particularly in the transcriptional regulation of Ifng." Additionally, thestudy found that Regnase-1 deficiency induces high expression of CXCR6 in
NK cells, a chemokine receptor of which expression is typically lost in maturemurine NK cells. Furthermore, IFN-γ-mediated induction of CXCL16 expression
in myeloid cells supports NK cell infiltration and persistence in the tumor
microenvironment via the CXCR6-CXCL16 axis.
In current cancer immunotherapy, immune checkpoint inhibitors such as antiPD-1 and anti-CTLA-4 antibodies have demonstrated significant therapeutic
efficacy against leukemias and lymphomas. However, unlike traditional
chemotherapies and kinase inhibitors, the results yielded by anti-tumor
immunotherapy for solid tumors have not been as promising. The findings ofthis study potentially overcome the challenges of immune checkpoint inhibitors
against solid tumors by promoting infiltration and persistence of immune cells
that have cytotoxic activity, such as NK cells and T cells, within the tumor
microenvironment. This approach augments the production of cytotoxic proteinssuch as IFN- γ, Granzymes, and Perforin from these immune cells. Additionally,targeting the expression or function of Regnase-1 in these immune cells sheds
light on the development of a promising strategy for anti-tumor immunotherapy.
Furthermore, combining the loss-of-function strategy targeting Regnase-1 withcurrent anti-tumor immunotherapies, such as immune checkpoint inhibitors andCAR-T cell therapy, has the potential to synergistically enhance therapeutic
efficacy against solid tumors.
###The article, “Deletion of the mRNA endonuclease Regnase-1 promotes NK cellanti-tumor activity via OCT2-dependent transcription of Ifng” was published inImmunity at DOI: https://doi.org/10.1016/j.immuni.2024.05.006

Summary: Research collaboration between Osaka University and Otsuka
Pharmaceutical Co., Ltd. revealed that deletion of mRNA endonuclease
Regnase-1 promoted NK cell anti-tumor activity via OCT2-dependenttranscriptional up-regulation of Ifng mRNA. Associated with the deletionof Regnase-1 in NK cells, NK cells showed a high expression of OCT2
and CXCR6 in those that escaped from mRNA decay from Regnase-1,
and they contributed to the transcriptional regulation of Ifng and NK cell
persistence inside the tumor microenvironment, respectively. The lossof-function strategy targeting Regnase-1 potentially enhances theproduction of cytotoxic proteins such as IFN-γ, granzymes, and perforin.
This approach also promotes NK cell infiltration and persistence within
the tumor, thereby facilitating the development of effective anti-tumor
immunotherapy against solid tumors.
Title: Deletion of the mRNA endonuclease Regnase-1 promotes NK cell antitumor activity via OCT2-dependent transcription of Ifng
Journal: Immunity
Authors: Xin Sun,* Yasuharu Nagahama,* Shailendra Kumar Singh, Yuuki
Kozakai, Hiroshi Nabeshima, Kiyoharu Fukushima, Hiroki Tanaka, Daisuke
Motooka, Eriko Fukui, Eric Vivier, Diego Diez, and Shizuo Akira***: equally contributed, **: correspondence
DOI: 10.1016/j.immuni.2024.05.006
Funded by:
Otsuka Pharmaceutical Co., Ltd.
Japan Science and Technology Agency (JST)Japan Agency for Medical Research and Development (AMED)
Website of Osaka University: https://resou.osaka-u.ac.jp/en
About Immunology Frontier Research Center (IFReC), Osaka University
IFReC was established by the support of the World Premier International
Research Center Initiative (WPI) in 2007. IFReC aims to overcome immunerelated diseases by clarifying the whole picture of the immune system, and has
promoted globally competitive fundamental research with excellent researchers
from overseas.
Website: https://www.ifrec.osaka-u.ac.jp/en/