HLA class I expression shapes the tumor immune microenvironment and influences prognosis in prostate cancer

Abstract

Background: Human leukocyte antigen (HLA) class I encompasses peptide-binding proteins that regulate T-cell interactions. We examined HLA class I expression in prostate cancers (PC), exploring associations with clinical outcomes, molecular features, and tumor immune microenvironment. Methods: We analyzed 8040 PC samples from the Caris Life Sciences database, stratifying them into HLA-high (upper quartile) and -low (lower quartile) groups. Genomic and transcriptomic alterations were compared. Immune cell fractions were inferred using quanTIseq, and overall survival (OS) data was obtained from insurance claims. Differences were computed with Cox proportional hazards. Results: Among 66 cancer types, PC ranked 3^rd-, 11^th-, and 19^th-lowest for HLA-A, -B, and -C expression, respectively. In PC, genes tied to androgen receptor (AR) signaling, immune checkpoint molecules (CTLA4, PD-L1), and the epithelial-mesenchymal transition were significantly higher in HLA-high tumors. HLA-high status was linked to greater tumor immune activity, marked by higher T cell fractions and enhanced immune hallmarks. HLA-high tumors were less likely to possess alterations in AR, FOXA1, and CDK12, but harbored increased alterations in tumor suppressor gene (RB1, PTEN) alterations. Tumors with high HLA-A and HLA-B had elevated TMB-H/MSI-H/dMMR status. Finally, shorter OS was observed in patients with high HLA-A or HLA-B expression, while longer OS was associated with high HLA-C expression. Conclusions: In PC, elevated HLA class I levels correlate with immune activity, molecular characteristics, and clinical outcomes. We suggest considering HLA expression as a supplementary marker of immune activity in PC, alongside genetic mutations and transcriptomic markers.