TCC-SUP

AR could Affect PD-L1 Expression in BCa Cells

Androgen receptor (AR) influences bladder cancer (BCa) initiation and progression, but its role in tumor immune escape remains unclear. While AR promotes BCa invasion and cisplatin resistance, whether it affects antitumor immunity by modulating immune cell killing is unknown. Liu's team focused on PD-L1, a critical immune checkpoint molecule and immunotherapy target.

TCGA data showed high AR signaling in the luminal papillary subtype, which is more common in male patients. Analysis of the TRGAted database revealed sex-specific prognostic differences for PD-L1: higher PD-L1 correlated with worse survival in males, particularly in early-stage (I-II) and non-metastatic disease, whereas females showed the opposite trend (Fig. 1A, B). In the luminal papillary subtype, elevated PD-L1 was significantly associated with poor survival in males but not females (Fig. 1C, D). High AR expression also predicted worse progression-free survival in luminal papillary and luminal infiltrated subtypes (Fig. 1E), with combined high AR/PD-L1 indicating the poorest outcomes (Fig. 1F).

To examine whether AR regulates PD-L1, they used T24 (low AR) and TCC-SUP (high AR) BCa cell lines. AR overexpression and androgen (DHT) treatment upregulated PD-L1 in T24 cells (Fig. 1G-I), while AR knockdown and antiandrogen (Enz) treatment downregulated PD-L1 in TCC-SUP cells (Fig. 1K). Additional antiandrogens (HF) and the AR degrader ASC-J9 similarly reduced PD-L1. Flow cytometry confirmed that membrane PD-L1 levels paralleled AR activity: DHT increased and Enz decreased surface PD-L1 expression (Fig. 1L-O). These data demonstrate that AR signaling regulates PD-L1 expression in BCa cells.