Immune checkpoint-related serum proteins and genetic variants predict outcomes of localized prostate cancer, a cohort study

• Published in: Cancer Immunology, Immunotherapy Vol. 70; no. 3; pp. 701 - 712
• Main Authors: Wang, Qinchuan, Ye, Yuanqing, Yu, Hao, Lin, Shu-Hong, Tu, Huakang, Liang, Dong, Chang, David W., Huang, Maosheng, Wu, Xifeng
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-03-2021; Springer Nature B.V
• Subjects: Aged; Biomarkers; BTLA protein; Cancer Research; CD223 antigen; CD27 antigen; CD28 antigen; CD80 antigen; Cohort analysis; Cohort Studies; CTLA-4 protein; Disease Progression; Disease Susceptibility; Gene expression; Genetic diversity; Genetic Variation; Genotype; Humans; Immune checkpoint; Immune Checkpoint Proteins - blood; Immune Checkpoint Proteins - genetics; Immune Checkpoint Proteins - metabolism; Immunology; Immunophenotyping; Kaplan-Meier Estimate; Male; Medicine; Medicine & Public Health; Middle Aged; Neoplasm Staging; Oncology; Original; Original Article; PD-1 protein; PD-L1 protein; Prognosis; Prostate cancer; Prostatic Neoplasms - etiology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - mortality; Prostatic Neoplasms - pathology; Proteins; Receptors, Antigen, B-Cell - metabolism; Serum levels; Serum proteins; Single-nucleotide polymorphism; Statistical analysis; Genetic variations; Serum immune checkpoint; Localized prostate cancer; Biochemical recurrence; Progression free survival; Aggressiveness
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02718-1

Background
The 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.
Methods
We 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.
Results
We 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.
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.