Phosphorylation and Stabilization of PD-L1 by CK2 Suppresses Dendritic Cell Function

PD-L1 磷酸化 功能(生物学) 癌症研究 细胞生物学 免疫系统 化学 生物 免疫疗法 免疫学 生物化学
作者
Xixi Zhao,Yongkun Wei,Yu‐Yi Chu,Yintao Li,Jung-Mao Hsu,Zhou Jiang,Chunxiao Liu,Jennifer L. Hsu,Wei‐Chao Chang,Ri‐Yao Yang,Li-Chuan Chan,Jingkun Qu,Shuqun Zhang,Haoqiang Ying,Dihua Yu,Mien‐Chie Hung
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:82 (11): 2185-2195 被引量:28
标识
DOI:10.1158/0008-5472.can-21-2300
摘要

Targeting immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has transformed cancer treatment, with durable clinical responses across a wide range of tumor types. However, a high percentage of patients fail to respond to anti-PD-1/PD-L1 treatment. A greater understanding of PD-L1 regulation is critical to improving the clinical response rate of PD-1/PD-L1 blockade. Here, we demonstrate that PD-L1 is phosphorylated and stabilized by casein kinase 2 (CK2) in cancer and dendritic cells (DC). Phosphorylation of PD-L1 at Thr285 and Thr290 by CK2 disrupted PD-L1 binding with speckle-type POZ protein, an adaptor protein of the cullin 3 (CUL3) ubiquitin E3 ligase complex, protecting PD-L1 from CUL3-mediated proteasomal degradation. Inhibition of CK2 decreased PD-L1 protein levels by promoting its degradation and resulted in the release of CD80 from DC to reactivate T-cell function. In a syngeneic mouse model, combined treatment with a CK2 inhibitor and an antibody against T-cell immunoglobulin mucin-3 (Tim-3) suppressed tumor growth and prolonged survival. These findings uncover a mechanism by which PD-L1 is regulated and suggest a potential antitumor treatment option to activate DC function by blocking the CK2-PD-L1 pathway and inhibiting Tim-3.This work identifies a role for CK2 in immunosuppression by phosphorylation and stabilization of PD-L1, identifying CK2 inhibition as an immunotherapeutic approach for treating cancer.
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