Abstract
BackgroundThe clinical predictors and biological mechanisms for localized prostate cancer (PCa) outcomes remain mostly unknown. We aim to evaluate the role of serum immune-checkpoint-related (ICK) proteins and genetic variations in predicting outcomes of localized PCa.MethodsWe profiled the serum levels of 14 ICK-related proteins (BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, Tim-3, CD28, CD80, 4-1BB, CD27, and CTLA-4) in 190 patients with localized PCa. The genotypes of 97 single nucleotide polymorphisms (SNPs) from 19 ICK-related genes were analyzed in an extended population (N = 1762). Meta-data from ArrayExpress and TCGA was employed to validate and to probe functional data. Patients were enrolled and tumor aggressiveness, biochemical recurrence (BCR), and progression information were obtained. Statistical analyses were performed analyzing associations between serum biomarkers, genotypes, mRNA and outcomes.ResultsWe showed that serum (s)BTLA and sTIM3 levels were associated with PCa aggressiveness (P < 0.05). sCD28, sCD80, sCTLA4, sGITR, sHVEM and sIDO correlated with both BCR and progression risks (all P < 0.05). We further identified ICK variants were significantly associated with aggressiveness, BCR and progression. Among them, 4 SNPs located in CD80 (rs7628626, rs12695388, rs491407, rs6804441) were not only associated with BCR and progression risk, but also correlated with sCD80 level (P < 0.01). rs491407 was further validated in an independent cohort. The CD80 mRNA expression was associated with BCR (HR, 1.85, 95% CI 1.06–3.22, P = 0.03) in meta-analysis of validation cohorts.ConclusionWe highlight the prognostic value of serum ICK-related proteins for predicting aggressiveness, BCR and progression of PCa. The genetic variations and mRNA expression in CD80 could be predictors and potential targets of localized PCa.
Highlights
Treatment of localized prostate cancer (PCa) is largely dependent on risk stratification based on aggressiveness [1]
Pathological Gleason score (GS) and serum prostate-specific antigen (PSA) are mainly applied in outcome prediction for PCa [2] but remain imperfect in predicting properties of the tumor and biochemical recurrence (BCR), which may lead to over-treatment in patients with indolent cancer [3]
Though Ipilimumab failed in the treatment of metastatic castration-resistant PCa in a recent clinical trial [4], combinatorial immunotherapy with Immune checkpoint blockade (ICB) and Myeloid-derived suppressor cells (MDSCs) targeted therapy showed efficacy in mCRPC
Summary
Treatment of localized prostate cancer (PCa) is largely dependent on risk stratification based on aggressiveness [1]. Pathological Gleason score (GS) and serum prostate-specific antigen (PSA) are mainly applied in outcome prediction for PCa [2] but remain imperfect in predicting properties of the tumor and biochemical recurrence (BCR), which may lead to over-treatment in patients with indolent cancer [3]. PD-L1 expression is independently associated with BCR in aggressive PCa [7] These studies implicate the involvement of ICK-related genes during PCa development. Conclusion We highlight the prognostic value of serum ICK-related proteins for predicting aggressiveness, BCR and progression of PCa. The genetic variations and mRNA expression in CD80 could be predictors and potential targets of localized PCa
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