Abstract
Background:
The PSMD11 has been shown to be associated with the malignant progression and clinical outcomes of various carcinomas. However, the molecular mechanism of PSMD11 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we investigated the molecular mechanism of PSMD11 effect on the immune escape in NSCLC.
Methods:
Co-culture models of NSCLC cells and T cells were constructed. Colony formation assays and flow cytometry were used to detect the proliferation and apoptosis of NSCLC cells in the co-culture system after the knock down of PSMD11. Western blotting was used to detect the expression of programmed death-ligand 1 (PD-L1) after the knock down of PSMD11. Co-immunoprecipitation (co-IP) assays were used to observe the interaction between PD-L1 and PSMD11 and USP14 in the A549 and H1299 cells. The in vivo effects of PSMD11 were analyzed using a xenograft tumor model.
Results:
In the NSCLC cell/T cell co-culture models, the knockdown of PSMD11 significantly upregulated T cell-mediated apoptosis and enhanced the killing effect of T cells in the A549 and H1299 cells, and also significantly upregulated the expression of killer T cell markers Granzyme and perforin in the T cells. We also found that the knockdown of PSMD11 inhibited the expression of PD-L1. The mass spectrometry (MS) and co-IP results showed that PSMD11 interacted with PD-L1 and the deubiquitinating enzyme USP14. Overexpression of USP14 leads to an increase in the protein level of PD-L1, while knocking down PSMD11 can reverse this elevated state. The overexpression of PD-L1 and USP14 in the NSCLC cells reversed the effects of PSM11 on immune escape. In vivo, the knockdown of PSMD11 promoted the anti-tumor effect of anti-PD-1 therapy.
Conclusions:
This study showed that PSMD11 recruits USP14 to modulate the deubiquitinating degradation of PD-L1 to promote immune escape in NSCLC.