Department of Oncology, the Affiliated Wujin Hospital of Jiangsu University, Changzhou, Jiangsu, 213017, P. R. China.
School of Life Science, Jiangsu University, Zhenjiang, Jiangsu, 212013, P. R. China.
Adv Sci (Weinh). 2023 Dec;10(34):e2304068. doi: 10.1002/advs.202304068. Epub 2023 Oct 23.
Immune cells can protect against tumor progression by killing cancer cells, while aberrant expression of the immune checkpoint protein PD-L1 (programmed death ligand 1) in cancer cells facilitates tumor immune escape and inhibits anti-tumor immunotherapy. As a serine/threonine kinase, CK2 (casein kinase 2) regulates tumor progression by multiple pathways, while it is still unclear the effect of CK2 on tumor immune escape. Here it is found that ING4 induced PD-L1 autophagic degradation and inhibites non-small cell lung cancer (NSCLC) immune escape by increasing T cell activity. However, clinical analysis suggests that high expression of CK2 correlates with low ING4 protein level in NSCLC. Further analysis shows that CK2 induce ING4-S150 phosphorylation leading to ING4 ubiquitination and degradation by JFK ubiquitin ligase. In contrast, CK2 gene knockout increases ING4 protein stability and T cell activity, subsequently, inhibites NSCLC immune escape. Furthermore, the combined CK2 inhibitor with PD-1 antibody effectively enhances antitumor immunotherapy. These findings provide a novel strategy for cancer immunotherapy.
免疫细胞可以通过杀死癌细胞来防止肿瘤进展，而癌细胞中免疫检查点蛋白 PD-L1（程序性死亡配体 1）的异常表达促进了肿瘤免疫逃逸，并抑制了抗肿瘤免疫治疗。作为丝氨酸/苏氨酸激酶，CK2（酪蛋白激酶 2）通过多种途径调节肿瘤进展，但其对肿瘤免疫逃逸的影响尚不清楚。本文发现，ING4 通过增加 T 细胞活性诱导 PD-L1 自噬降解并抑制非小细胞肺癌（NSCLC）免疫逃逸。然而，临床分析表明，CK2 在 NSCLC 中的高表达与 ING4 蛋白水平低相关。进一步的分析表明，CK2 诱导 ING4-S150 磷酸化，导致 JFK 泛素连接酶介导的 ING4 泛素化和降解。相比之下，CK2 基因敲除增加了 ING4 蛋白的稳定性和 T 细胞活性，从而抑制了 NSCLC 免疫逃逸。此外，CK2 抑制剂与 PD-1 抗体联合使用能有效增强抗肿瘤免疫治疗。这些发现为癌症免疫治疗提供了一种新策略。
