Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT-PD-L1 Axis
Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT-PD-L1 Axis
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DOI：
10.1002/advs.202304342
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发表时间：
2024-01-16
期刊：
影响因子：
15.1
通讯作者：
Wang，Xiaojian
中科院分区：
文献类型：
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作者：
Wang，Ning;Jiang，Yu;Wang，Xiaojian
针对PD-L1的免疫治疗对多种高度不可预测的肿瘤仍然无效。采用联合免疫治疗和另一种靶向治疗是克服这种治疗耐药性的可行方法。在此，在小鼠同基因模型中观察到肿瘤细胞中丝氨酸苏氨酸激酶STK24的缺失导致肿瘤生长显著减弱，这一过程依赖于细胞毒CD8+T细胞和NK细胞。在机制上，肿瘤细胞中的STK24与Thr21处的AKT结合并直接磷酸化AKT，从而促进AKT的激活和随后的PD-L1诱导。相反，STK24的缺失或抑制可以阻断干扰素-γ介导的PD-L1的表达。各种小鼠模型表明，体内沉默STK24可以显著增强抗PD-1阻断策略的效果。在多种肿瘤类型的患者标本中观察到STK24水平升高，并与肿瘤内细胞毒性CD8+T细胞的浸润和患者生存呈负相关。这项研究共同确认STK24是抗肿瘤免疫的关键调节剂，参与AKT和PD-L1/PD-1信号转导，是联合免疫治疗的一个有前景的靶点。
Immunotherapy targeting PD‐L1 is still ineffective for a wide variety of tumors with high unpredictability. Deploying combined immunotherapy with alternative targeting is practical to overcome this therapeutic resistance. Here, the deficiency of serine‐threonine kinase STK24 is observed in tumor cells causing substantial attenuation of tumor growth in murine syngeneic models, a process relying on cytotoxic CD8+T and NK cells. Mechanistically, STK24 in tumor cells associates with and directly phosphorylates AKT at Thr21, which promotes AKT activation and subsequent PD‐L1 induction. Deletion or inhibition of STK24, by contrast, blocks IFN‐γ‐mediated PD‐L1 expression. Various murine models indicate that in vivo silencing of STK24 can significantly enhance the efficacy of the anti‐PD‐1 blockade strategy. Elevated STK24 levels are observed in patient specimens in multiple tumor types and inversely correlated with intratumoral infiltration of cytotoxic CD8+T cells and with patient survival. The study collectively identifies STK24 as a critical modulator of antitumor immunity, which engages in AKT and PD‐L1/PD‐1 signaling and is a promising target for combined immunotherapy.