Division of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan.
J Cell Physiol. 2022 Sep;237(9):3587-3597. doi: 10.1002/jcp.30817. Epub 2022 Jul 29.
A high basal level of autophagic flux in bladder cancer (BC) cells prevents cell death and weakens chemotherapy efficacy. However, how autophagy influences cancer-associated immunosuppression in BC remains undetermined. In this study, we observed a negative correlation between the autophagy-related markers LC3-II and programmed death ligand-1 (PD-L1) in BC cells. The autophagy inhibitors chloroquine (CQ) and bafilomycin A1 (Baf-A1) increased PD-L1 expression in BC cells through the ERK-JNK-c-Jun signal-transduction pathway. Moreover, the treatment of BC cells with CQ and Baf-A1 inhibited hsa-microRNA-34a (miR-34a) expression and miR-34a overexpression in BC cells prevented the autophagy blockade-induced PD-L1 expression; a negative correlation between miR-34a and PD-L1 expression was observed during treatment with autophagy inhibitors. Furthermore, miR-34a overexpression induced the cytotoxic activity of natural killer cells against BC cells. Our results provide evidence that autophagy blockade and its regulatory pathway affect cancer-associated immunosuppression through PD-L1 elevation. Thus, the coadministration of autophagy inhibitors and a PD-L1 immune checkpoint blockade provides a potential therapeutic approach for treating BC.
在膀胱癌 (BC) 细胞中，高基础自噬通量可防止细胞死亡并削弱化疗效果。然而，自噬如何影响 BC 中的癌症相关免疫抑制仍未确定。在本研究中，我们观察到 BC 细胞中的自噬相关标志物 LC3-II 和程序性死亡配体-1 (PD-L1) 呈负相关。自噬抑制剂氯喹 (CQ) 和巴弗洛霉素 A1 (Baf-A1) 通过 ERK-JNK-c-Jun 信号转导通路增加 BC 细胞中的 PD-L1 表达。此外，CQ 和 Baf-A1 处理 BC 细胞可抑制 hsa-微 RNA-34a (miR-34a) 的表达，而 miR-34a 在 BC 细胞中的过表达可防止自噬阻断诱导的 PD-L1 表达；在用自噬抑制剂治疗期间观察到 miR-34a 和 PD-L1 表达之间呈负相关。此外，miR-34a 的过表达诱导自然杀伤细胞对 BC 细胞的细胞毒性活性。我们的研究结果提供了证据表明，自噬阻断及其调节途径通过上调 PD-L1 影响癌症相关免疫抑制。因此，自噬抑制剂和 PD-L1 免疫检查点抑制剂的联合给药为治疗 BC 提供了一种潜在的治疗方法。
