HLA Class I Expression is Associated with Increased Immune Cell Density and PTEN Loss in Prostate Cancer

Human leukocyte antigen Class I (HLA-I) downregulation in prostate cancer may contribute to tumor immune evasion. We digitally quantified HLA-I protein expression in a cohort of racially diverse and molecularly characterized prostatectomy specimens, as well as additional cohorts of metastatic hormone-sensitive (mHSPC) and castration-resistant prostate cancer (mCRPC). We confirm that HLA-I protein expression is negatively associated with intragenic methylation of major HLA-I genes, downregulated in tumor compared to benign glands, but not associated with race, genetic ancestry or clinicopathologic parameters in primary prostate cancer. Compared to matched primary tumor tissue, HLA-I expression is higher in HSPC pelvic lymph node metastases and increased primary tumor expression is inversely associated with metastasis among self-identified White, but not Black, patients. HLA-I expression in primary tumors is positively correlated with infiltrating immune cell densities, consistent with its established role in tumor cell immunogenicity. Surprisingly, primary tumors with PTEN loss show significantly higher HLA-I expression than those with intact PTEN, and this finding is validated in pre-clinical cell line and animal models, with a similar (nonsignificant) trend in mCRPC. Implications: The novel finding that PTEN loss is associated with higher tumoral HLA-I expression is concordant with observed increased immune cell infiltrates in tumors lacking PTEN, and may be relevant for precision medicine therapeutic approaches.