Autophagy blockade potentiates cancer‐associated immunosuppression through programmed death ligand‐1 upregulation in bladder cancer

• Published in: Journal of cellular physiology 2022-09, Vol.237 (9), p.3587-3597
• Main Authors: Tsai, Te‐Fu, Chang, An‐Chen, Chen, Po‐Chun, Ho, Chao‐Yen, Chen, Hung‐En, Chou, Kuang‐Yu, Hwang, Thomas I‐Sheng
• Format: Article
• Language: English
• Subjects: Apoptosis; Autophagy; Bladder; Bladder cancer; Cancer; Cell death; Chemotherapy; Chloroquine; Cytotoxicity; Hsa‐miR‐34a; Immune checkpoint; Immunosuppression; Inhibitors; Ligands; miRNA; Mortality; Natural killer cells; PD-L1 protein; PD‐L1; Ribonucleic acid; RNA
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30817

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. Graphical Our model illustrates the pharmacological inhibition of autophagy could induce PD‐L1 expression in BC cells through the ERK–JNK–c‐Jun signaling transduction pathway and miR‐34a downregulation, revealing the effect of genetic and epigenetic regulation of autophagy on PD‐L1. In consequence, BC cells expressing PD‐L1 suppress NK cell cytotoxic activity.