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 prostate cancer (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 with benign glands, but not associated with race, genetic ancestry, or clinicopathologic parameters in primary prostate cancer. Compared with 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 patients, 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 preclinical cell line and animal models, with a similar (nonsignificant) trend in mCRPC.