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Phosphorylation and Stabilization of PD-L1 by CK2 Suppresses Dendritic Cell Function
Xixi Zhao1,2,3, Yongkun Wei1, Yu-Yi Chu1
1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Abstract:
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.
Insights
Casein kinase 2 (CK2) stabilizes programmed cell death ligand 1 (PD-L1) in cancer cells. Inhibiting CK2 reduces PD-L1, enhancing anti-cancer immune responses and improving survival in mouse models.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Oncology
Background:
- Immune checkpoint inhibitors like anti-PD-1/PD-L1 therapies have revolutionized cancer treatment but face limitations due to patient non-response.
- Understanding the regulation of programmed cell death ligand 1 (PD-L1) is crucial for improving the efficacy of these therapies.
- Dendritic cells (DC) play a key role in initiating anti-tumor immune responses.
Purpose of the Study:
- To elucidate the regulatory mechanisms of PD-L1 stability and its impact on anti-tumor immunity.
- To investigate the role of casein kinase 2 (CK2) in PD-L1 regulation.
- To explore novel therapeutic strategies targeting the CK2-PD-L1 pathway for cancer treatment.
Main Methods:
- Investigated the phosphorylation and stabilization of PD-L1 by CK2 in cancer cells and DCs.
- Utilized CK2 inhibitors to assess the impact on PD-L1 protein levels and degradation.
- Examined the effect of CK2 inhibition on CD80 release from DCs and T-cell re-activation.
- Evaluated the efficacy of combined CK2 inhibition and anti-T-cell immunoglobulin mucin-3 (Tim-3) therapy in a syngeneic mouse tumor model.
Main Results:
- CK2 phosphorylates and stabilizes PD-L1 by preventing its binding to the CUL3 ubiquitin ligase complex, thus inhibiting proteasomal degradation.
- Inhibition of CK2 leads to decreased PD-L1 protein levels through enhanced degradation.
- CK2 inhibition promotes the release of CD80 from DCs, restoring T-cell function.
- Combined treatment with a CK2 inhibitor and an anti-Tim-3 antibody suppressed tumor growth and improved survival in mice.
Conclusions:
- CK2 plays a significant role in cancer cell and DC immunosuppression by stabilizing PD-L1.
- CK2 inhibition represents a promising immunotherapeutic strategy to enhance anti-tumor immunity by reducing PD-L1 levels and reactivating T-cells.
- Targeting the CK2-PD-L1 pathway, in combination with Tim-3 inhibition, offers a potential new treatment option for cancer.
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