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.
Molecular cancer research : MCR. 2026 May 01 [Epub ahead of print]
Adrianna Amaral, Thiago Vidotto, Juhyung Woo, Michael Rubenstein, Jiayun Lu, Carolina Gomes-Alexandre, Angelo M De Marzo, Karen Sfanos, Janielle Maynard, Ezra Baraban, Laura A Sena, Mark C Markowski, Emmanuel S Antonarakis, Corinne Joshu, Kaushal Asrani, Tamara L Lotan
Johns Hopkins University Baltimore, MD United States., Johns Hopkins University Baltimore, Maryland United States., Johns Hopkins Medicine Baltimore, Maryland United States., Johns Hopkins Medicine Baltimore United States., Johns Hopkins University United States., Johns Hopkins Medicine Baltimore, MD United States., University of Minnesota Minneapolis United States., Johns Hopkins Bloomberg School of Public Health Baltimore, MD United States.