Effect of HLA class I expression on the tumor immune microenvironment and prognosis in prostate cancer.

5044 Background: Human leukocyte antigen (HLA) class I comprises a family of peptide-binding proteins that regulate T-cell interactions. Here, we examined HLA class I mRNA expression and gene zygosity in prostate cancers (PCs), exploring associations with clinical outcomes, molecular features, and tumor microenvironment. Methods: We analyzed 10,790 PC samples, of which 8,040 (75%) contained HLA transcription data, and 2,792 (26%) contained HLA genotypes in the Caris Life Sciences database. Samples were stratified into HLA-high (>75th percentile) and -low (<25th percentile) groups. Genomic and transcriptomic alterations were compared at an adjusted significance level of 0.05. Immune cell fractions were inferred by quanTIseq. Overall survival was obtained from insurance claims data and computed using Cox proportional hazards. Results: Among 66 cancer types, PC ranked 2nd, 11th, and 19th lowest with respect to HLA-A, HLA-B, and HLA-C expression. In PC, genes related to AR signaling, immunoglobulins, and cell-surface antigens (CTLA4, PD-L1, TROP2, B7-H3, and PSMA) were significantly increased in HLA-high tumors. HLA-high status was associated with increased interferon-gamma scores and more cytotoxic and regulatory T cells, B cells, and NK cells. HLA-high tumors also exhibited a 2-fold depletion in CDK12 and AR/FOXA1 mutations but were enriched in tumor suppressor gene (RB1, PTEN) alterations. HLA-A high tumors exhibited increases in MSI-H/dMMR status (4.8% vs. 3.3% and 5.1% vs 3.1%, p=0.04 and 0.01), while dMMR was also increased in HLA-B high tumors (5.1% vs. 3.4%, p=0.03). HLA class I expression was generally lower in metastatic biopsies (Bx) compared to primary prostate Bx. Upon examining the zygosity of HLA alleles, metastatic Bx exhibited a higher proportion of homozygous HLA-B (7.2% vs. 5.1%, p=0.03) compared to prostate Bx. Last, worse overall survival was seen in prostate Bx that were high in HLA-A or HLA-B (HR = 1.36, 1.21, p<0.0001, 0.008) or metastatic Bx that were HLA-A high (HR = 1.18, p = 0.019). Conclusions: HLA class I expression is lower in PCs compared to other cancers, but elevated HLA class I levels correlate with immune cell activity, somatic alterations, and clinical outcomes. Unexpectedly, HLA-A and HLA-B high tumors portended shorter survival, perhaps due to significant enrichment of PTEN/RB1 alterations. Altogether, HLA status, immunogenicity, and tumor suppressor alterations should be considered in tandem when considering patient prognosis.