Prostate cancer disease recurrence after radical prostatectomy is associated with HLA type and local cytomegalovirus immunity

Abstract

Prostate cancer is a heterogeneous disease with a need for new prognostic biomarkers. Human leukocyte antigen (HLA) genes are highly polymorphic genes central to antigen presentation to T‐cells. Two alleles, HLA‐A*02:01 and HLA‐A*24:02, have been associated with prognosis in patients diagnosed with de novo metastatic prostate cancer. We leveraged the next‐generation sequenced cohorts CPC‐GENE and TCGA‐PRAD to examine HLA alleles, antiviral T‐cell receptors and prostate cancer disease recurrence after prostatectomy. Carrying HLA‐A*02:01 (111/229; 48% of patients) was independently associated with disease recurrence in patients with low‐intermediate risk prostate cancer. HLA‐A*11 (carried by 42/441; 10% of patients) was independently associated with rapid disease recurrence in patients with high‐risk prostate cancer. Moreover, HLA‐A*02:01 carriers in which anti‐cytomegalovirus T‐cell receptors (CMV‐TCR) were identified in tumors (13/144; 10% of all patients in the cohort) had a higher risk of disease recurrence than CMV‐TCR‐negative patients. These findings suggest that HLA‐type and CMV immunity may be valuable biomarkers for prostate cancer progression.

The role of cytomegalovirus in prostate cancer incidence and mortality

“…We also found a positive association between a high CMV IgG VirScore in prostate tissue 14,30 , reflecting presence and diversity of CMV IgG antibodies, with CMV-pp71 epithelial abundance (n=15, p=0.003) (Figure 1B), further supporting an association between CMV immunity and epithelial CMV infection. Prostates of CMV seropositive donors did not have higher prevalence of inflammatory infiltrates with lymphocytes than in CMV seronegative donors (Figure S1A).…”

“…Ethical permission for study of human samples was granted by the regional ethics committee of Sweden (2010/313-31/3). Prostate tissue and blood samples were collected from post-mortem donors between 2015 and 2020 through KI Donatum, Karolinska Institutet, Stockholm, Sweden, as described in 14 and 9 ; post-mortem cohort.…”

“…In the US NHANES III cohort, CMV seropositive men had increased cancer mortality 13 , but it is unknown if CMV serostatus is specifically associated with prostate cancer mortality. We recently reported that local CMV T-cell immunity in the prostate is associated with disease recurrence after radical prostatectomy in carriers of the common allele HLA-A*02-01 14 . Moreover, experimental CMV inhibition in models of prostate cancer can induce growth arrest and programmed cell death 9 .…”

Human Cytomegalovirus Protein Expression Is Correlated with Shorter Overall Survival in Breast Cancer Patients: A Cohort Study

“…A correlation between HCMV presence in tumors and survival was first observed in patients with glioblastoma [ 61 ]. Several studies then indicated that HCMV is associated with higher malignancy grade and poor outcome not only in patients with glioblastoma and but also in patients with breast, colon, ovarian and prostate cancer [ 62 , 63 , 64 , 65 , 66 ]. If the virus plays a role as a tumor promoting agent for various cancer forms, viral protein expression should be considered and evaluated as a prognostic marker, and this could open for new therapeutic possibilities for patients.…”

Association of HLA-A*11:01, -A*24:02, and -B*18:01 with Prostate Cancer Risk: A Case-Control Study

“…This suggests that individuals harboring these particular genetic polymorphisms are at an elevated risk of experiencing post-surgical advancement of their prostate malignancy. Consequently, distinct immunogenetic profiles may serve as prognostic markers, offering a nuanced understanding of disease trajectory in prostate cancer [29][30][31]. In the present study, we applied NGS Illumina technology to genotype two HLA class I loci (HLA-A and HLA-B) in patients with PCa and healthy controls (HCs).…”