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J. Adv. Res., May 31 2025, S2090-1232(25)00379-0 | https://doi.org/10.1016/j.jare.2025.05.058
Enhancement of NK cell activity via DNA-sensing inhibition by Poxin transgene
Ling-Zu Kong a,b, Seok-Min Kim a, Soo Yun Lee a, In-Hwan Jang a, Chunli Wang c, Seona Jo a,d, Se-Chan Oh a, Sunyoung Lee a,e, Ji Hyun Kim a,d, Kee K. Kim b, Tae-Don Kim a,d,f,g
aCenter for Cell and Gene Therapy, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
bDepartment of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 34134, Republic of Korea
cKey Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China
dDepartment of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea
eDepartment of Life Sciences, Korea University, Seoul 02841, Republic of Korea
fBiomedical Mathematics Group, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea
gDepartment of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
Corresponding author : Tae-Don Kim
aCenter for Cell and Gene Therapy, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
bDepartment of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 34134, Republic of Korea
cKey Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China
dDepartment of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea
eDepartment of Life Sciences, Korea University, Seoul 02841, Republic of Korea
fBiomedical Mathematics Group, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea
gDepartment of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
Corresponding author : Tae-Don Kim
Abstract
Introduction
Natural Killer (NK) cell therapy has shown strong potential for cancer treatment; however, NK cell efficacy is limited by their short lifespan and suppression within the tumor microenvironment. One factor contributing to this suppression may be the activation of the cyclic GMP-AMP synthase (cGAS) pathway. Since the discovery of cGAS as a DNA sensor, there has been renewed interest in DNA sensing mechanisms, although the role of DNA sensing-mediated innate immune responses on NK cells remains unclear. Poxin, a protein derived from DNA viruses, is known to degrade the cGAS signaling product cyclic GMP-AMP (cGAMP) and could potentially alleviate DNA sensing-related stress in NK cells.
Natural Killer (NK) cell therapy has shown strong potential for cancer treatment; however, NK cell efficacy is limited by their short lifespan and suppression within the tumor microenvironment. One factor contributing to this suppression may be the activation of the cyclic GMP-AMP synthase (cGAS) pathway. Since the discovery of cGAS as a DNA sensor, there has been renewed interest in DNA sensing mechanisms, although the role of DNA sensing-mediated innate immune responses on NK cells remains unclear. Poxin, a protein derived from DNA viruses, is known to degrade the cGAS signaling product cyclic GMP-AMP (cGAMP) and could potentially alleviate DNA sensing-related stress in NK cells.
Objectives
This study aims to investigate whether Poxin expression can inhibit DNA sensing pathways in NK cells, thereby enhancing their cytotoxic function and anti-tumor activity.
Methods
We generated NK-92 cells expressing a Poxin transgene and evaluated their response to DNA sensing activation. The cGAS-STING pathway was stimulated through either exogenous plasmid transfection or irradiation to induce endogenous double-stranded DNA (dsDNA). We assessed NK-92 and umbilical cord blood derived primary NK (pNK) cells activity through cytotoxicity assay and analysis of perforin and granzyme B expression levels, performed RNA-seq analysis to explore the mechanism and conducted functional assays to evaluate anti-tumor efficacy of NK-92 and chimeric antigen receptors (CAR)-NK-92 cells.
Results
Poxin expression significantly inhibited the cGAS-STING pathway, reducing activation in response to both plasmid transfection and irradiation-induced dsDNA. RNA-seq analysis indicated increased levels of cytotoxic mediators, including perforin and granzyme B, in Poxin-expressing NK-92 cells. Furthermore, these transgenic NK-92/CAR-NK-92 cells exhibited enhanced anti-tumor activity compared to controls.
Conclusion
Poxin effectively suppresses DNA sensing-mediated innate immunity in NK cells, enhancing their cytotoxicity and anti-tumor effectiveness.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-06-05)
- 국내(교신)+국외 연구진
- 바이오·의료융합 > 바이오소재
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