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WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function

 Hyun Ju Yoon  ;  Gi-Cheon Kim  ;  Sejin Oh  ;  Hakhyun Kim  ;  Yong Keon Kim  ;  Yunji Lee  ;  Min Seo Kim  ;  Gino Kwon  ;  Yeon-Su Ok  ;  Ho-Keun Kwon  ;  Hyun Seok Kim 
 EXPERIMENTAL AND MOLECULAR MEDICINE, Vol.54(11) : 1913-1926, 2022-11 
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Animals ; B7-H1 Antigen* / genetics ; CD8-Positive T-Lymphocytes* / immunology ; Cell Line, Tumor ; Humans ; Immunotherapy ; Lung Neoplasms* / genetics ; Mice ; Protein Serine-Threonine Kinases* / genetics ; Protein Serine-Threonine Kinases* / metabolism
Immune checkpoint therapies, such as programmed cell death ligand 1 (PD-L1) blockade, have shown remarkable clinical benefit in many cancers by restoring the function of exhausted T cells. Hence, the identification of novel PD-L1 regulators and the development of their inhibition strategies have significant therapeutic advantages. Here, we conducted pooled shRNA screening to identify regulators of membrane PD-L1 levels in lung cancer cells targeting druggable genes and cancer drivers. We identified WNK lysine deficient protein kinase 3 (WNK3) as a novel positive regulator of PD-L1 expression. The kinase-dead WNK3 mutant failed to elevate PD-L1 levels, indicating the involvement of its kinase domain in this function. WNK3 perturbation increased cancer cell death in cancer cell-immune cell coculture conditions and boosted the secretion of cytokines and cytolytic enzymes, promoting antitumor activities in CD4+ and CD8+ T cells. WNK463, a pan-WNK inhibitor, enhanced CD8+ T-cell-mediated antitumor activity and suppressed tumor growth as a monotherapy as well as in combination with a low-dose anti-PD-1 antibody in the MC38 syngeneic mouse model. Furthermore, we demonstrated that the c-JUN N-terminal kinase (JNK)/c-JUN pathway underlies WNK3-mediated transcriptional regulation of PD-L1. Our findings highlight that WNK3 inhibition might serve as a potential therapeutic strategy for cancer immunotherapy through its concurrent impact on cancer cells and immune cells.
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Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Ho-Keun(권호근) ORCID logo https://orcid.org/0000-0003-3175-0376
Kim, Gi-Cheon(김기천)
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
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