| Autor: |
Xixi Zhao, Yongkun Wei, Yu-Yi Chu, Yintao Li, Jung-Mao Hsu, Zhou Jiang, Chunxiao Liu, Jennifer L. Hsu, Wei-Chao Chang, Riyao Yang, Li-Chuan Chan, Jingkun Qu, Shuqun Zhang, Haoqiang Ying, Dihua Yu, Mien-Chie Hung |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Cancer research. 82(11) |
| ISSN: |
1538-7445 |
| Popis: |
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. Significance: 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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