PLA2G7 promotes immune evasion of bladder cancer through the JAK-STAT-PDL1 axis.

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.