The Effect of Human Leukocyte Antigen Genotype on Survival in Advanced Prostate Cancer Treated with Primary Androgen Deprivation Therapy: the KYUCOG-1401-A Study

Background Immune editing, in which human leukocyte antigens (HLA) have critical roles, has been suggested to shape the landscape of human cancer. This study prospectively investigated whether HLA gene zygosity is associated with the prognosis of primary androgen deprivation therapy in advanced prostate cancer. Methods KYUCOG-1401-A was conducted in conjunction with a prospective clinical trial (KYUCOG-1401). Among the patients enrolled in KYUCOG-1401 and treated with primary androgen deprivation therapy, only Japanese patients were included. HLA genotypes of HLA-A, B, C, DRB1, DQB1, and DPB1 were determined. The effect of divergence of HLA genotypes on time to progression, prostate cancer-specific survival, and overall survival was evaluated. Results Among 127 patients, homozygosity for HLA-DRB1 (HR, 95% CI; 4.05, 1.54–10.7, P = 0.0047) and HLA-DQB1 (HR, 95% CI; 3.75, 1.47–9.58, P = 0.0058) was associated with an increased risk of prostate cancer-specific mortality. Patients with higher HLA evolutionary divergence scores at HLA-DQB1 (HR, 95% CI; 0.90, 0.82–0.97, P = 0.0093) had lower risks of prostate cancer-specific mortality. Androgen-responsive gene sets were upregulated in CD4low and CD8low tumors in the prostate cancer cohort, but not in the bladder and kidney cancer cohorts. Conclusions This study suggested that the diversity of HLA-II loci including HLA-DRB1 and HLA-DQB1 plays an important role in advanced prostate cancer survival, contributing to improved risk stratification in advanced prostate cancer. Moreover, it was shown that CD4 + T cells play an important role in androgen deprivation therapy, suggesting that immunotherapy targeting CD4 + T cells is promising for prostate cancer.