232P - The immunosuppressive features of the 20S Proteasome β-subunit gene family in von Hippel-Lindau (VHL)-mutated clear cell renal cell carcinoma (ccRCC): A TCGA-based bioinformatics study

Background

An ongoing field of research examines the use of the proteasome genes as prognostic biomarkers in cancer. The cross talk between such machinery and VHL is well rectified, so it is of a great interest to study the prognostic utility of the 20S proteasome gene family in VHL-mutated ccRCC cohort.

Methods

Clinical and transcriptomics data of VHL-mutated ccRCC patients were obtained from the Cancer Genome Atlas Program (TCGA). A total of 11 genes of the 20S proteasome β-subunit (PSMB1-11) were retrieved and tested for their prognostic potential using multivariate Cox logistic regression. The immune suppressive landscape was viewed through the assessment of M2 macrophages (M2M), cancer-associated fibroblasts (CAF), T-regulatory cells (Tregs), and myeloid-derived suppressor cells (MDSC) infiltration using xCell. Correlations with T-cell exhaustion genes were performed additionally.

Results

A total of six genes exhibited significant prognostic indicators, including PSMB1 (HR: 2.113, 95% CI: 1.101-4.056, P = .024), PSMB2 (HR: 2.303, 95% CI: 1.168-4.542, P = .016), PSMB4 (HR: 2.165, 95% CI: 1.075-4.361, P = .031), PSMB6 (HR: 2.956, 95% CI: 1.458-5.998, P = .003), PSMB7 (HR: 2.168, 95% CI: 1.127-4.170, P = .020), and PSMB10 (HR: 2.227, 95% CI: 1.109-4.469, P = .024). Immunosuppressive cells infiltration analysis revealed the following significant correlations (P < .05): PSMB1: MDSC (ρ = 0.316), PSMB2: M2M (ρ = 0.242) and MDSC (ρ = 0.268), PSMB4: M2M (ρ = 0.159) and MDSC (ρ = 0.372), PSMB6: M2M (ρ = 0.247) and MDSC (ρ = 0.412), PSMB7: MDSC (ρ = 0.298), and PSMB10: M2M (ρ = 0.283) and MDSC (ρ = 0.271). No significant correlations were observed in CAF infiltration. Surprisingly, all the markers negatively correlated with Tregs infiltration. The prognostic genes followed a unified pattern of correlation with T-cell exhaustion genes in which positive significant correlations to CTLA4, LAG3, and GZMB were observed. In contrast, all the markers negatively correlated with CD274 (PD-L1) expression.

Conclusions

Several members of the 20S proteasome β-subunit gene family exhibit a prognostic role in VHL-mutated ccRCC and induce an immunosuppressive tumor microenvironment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.