Journal Article

Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT‐PD‐L1 Axis

Li, Mengjie, Li, Xu, Wang, Ning, Wang, Haofei, Zhou, Xuefei, Xu, Yunyang, Lin, Wenlong, Xie, Shaofang, Tang, Yang, Wang, Xiaojian, Xu, Pinglong, Pan, Jie, Jiang, Yu

2024

Overview

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. Immunotherapy targeting PD‐L1 is ineffective in many tumors and with inherent unpredictability. Substantial efforts are being channeled toward identifying novel targets to enhance immunotherapy efficacy through combination treatments. Here, STK24 is identified as a promoter of tumorigenesis in a non‐cancer cell‐autonomous manner. STK24 phosphorylates AKT at a previously unrecognized Thr21, augments PD‐L1 expression, and facilitates the evasion against antitumor immunity.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: AKT / Animals / Apoptosis / B7-H1 Antigen - metabolism / CD8-Positive T-Lymphocytes / Cell death / Cell growth / Cell Line, Tumor / Colorectal cancer / Cytotoxicity / Gastric cancer / Gene expression / Humans / Immunocompetence / Immunotherapy / Kinases / Lung cancer / Medical prognosis / Mice / Patients / programmed cell death ligand 1 (PD‐L1) / Protein expression / Proteins / Proto-Oncogene Proteins c-akt - metabolism / serine/threonine protein kinase 24 (STK24) / Statistical analysis / Tumor Escape / tumor immune evasion / Tumorigenesis / Tumors