Peng Ding, Yang Wuping, Tang Tianyu, He Anbang, Xu Xin, Jing Taile, Xia Dan
Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, PR China.
Cell Death Dis. 2025 Apr 1;16(1):234. doi: 10.1038/s41419-025-07593-1.
Targeting immune checkpoints such as Programmed death ligand-1 (PD-L1) and Programmed cell death 1 (PD-1) has been approved for treating bladder cancer and shows promising clinical benefits. However, the relatively low response rate highlights the need to seek an alternative strategy to traditional PD-1/PD-L1 targeting immunotherapy. In this study, we found that PLA2G7 is significantly elevated in bladder cancer and correlates with worse prognosis. In vitro experiments demonstrated that knockdown of PLA2G7 does not significantly affect the proliferation, migration, and invasion of bladder cancer cells. Flow cytometry detection, as well as protein and RNA detection, showed that knockdown of PLA2G7 significantly inhibits PD-L1 expression and suppresses the growth of transplanted tumors by promoting CD8 + T-cell infiltration. Further experiments showed that PLA2G7 regulates the JAK-STAT pathway to promote PD-L1 expression by upregulating the phosphorylation of STAT1 and STAT3. Meanwhile, results from syngeneic mouse models indicated that PLA2G7 suppression and anti-CTLA4 therapy have synergistic effects on tumor burden and mouse survival. In addition, we found that ETS1 promotes PLA2G7 overexpression in bladder cancer cells. In summary, our findings provide a novel immunotherapeutic strategy against bladder cancer through targeting the ETS1-PLA2G7-STAT1/STAT3-PD-L1 axis.
靶向程序性死亡配体1（PD-L1）和程序性细胞死亡蛋白1（PD-1）等免疫检查点已被批准用于治疗膀胱癌，并显示出有前景的临床益处。然而，相对较低的应答率凸显了寻求替代传统PD-1/PD-L1靶向免疫疗法策略的必要性。在本研究中，我们发现磷脂酶A2第VII组（PLA2G7）在膀胱癌中显著升高，且与较差的预后相关。体外实验表明，敲低PLA2G7对膀胱癌细胞的增殖、迁移和侵袭没有显著影响。流式细胞术检测以及蛋白质和RNA检测表明，敲低PLA2G7可显著抑制PD-L1表达，并通过促进CD8 + T细胞浸润来抑制移植瘤的生长。进一步实验表明，PLA2G7通过上调信号转导和转录激活因子1（STAT1）和信号转导和转录激活因子3（STAT3）的磷酸化来调节JAK-STAT信号通路，从而促进PD-L1表达。同时，同基因小鼠模型的结果表明，抑制PLA2G7与抗细胞毒性T淋巴细胞相关抗原4（CTLA4）疗法对肿瘤负荷和小鼠存活具有协同作用。此外，我们发现ETS1促进膀胱癌细胞中PLA2G7的过表达。总之，我们的研究结果通过靶向ETS1-PLA2G7-STAT1/STAT3-PD-L1轴，为膀胱癌提供了一种新的免疫治疗策略。
