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

Abstract

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.

BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia

“…Upon engagement, HVEM provides pro-survival and proliferative signals through activation of NF-kB transcriptional pathways, whereas BTLA negatively regulates T cell-mediated responses [ 36 , 37 , 38 , 39 ]. Further, aberrant surface expression and levels of soluble BTLA (sBTLA) in sera have been related to prognosis in various solid tumors and hematological malignancies [ 36 , 37 , 38 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. BTLA blockade, alone or in combination with chemotherapy, led to improved survival in epithelial ovarian carcinoma murine models [ 48 ].…”

Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice

“…Although the role of HVEM in T cell activation is well established, the role of HVEM expressed by tumor cells on the immune system is not clear. Several clinical studies have shown that HVEM expression is upregulated in many types of cancers including colorectal cancers [ 16 ], melanomas [ 17 ], esophageal carcinomas [ 18 ], gastric cancers [ 19 ], hepatocarcinomas [ 20 ], breast cancers [ 21 ], lymphomas [ 22 ], and PCa [ 23 ]. In these studies, a worse prognosis and lower survival of patients correlated with high levels of HVEM expression in the tumors or with elevated detection of soluble HVEM in the serum.…”

“…Similarly, upregulated expression of BTLA on CD8 + or CD4 + T cells or increased levels of soluble BTLA were associated with unfavorable prognosis for gallbladder cancer [ 26 ], diffuse large-B cell lymphoma [ 27 ], clear cell renal cell cancer [ 27 ], and prostate cancer patients [ 23 ]. Moreover, we have shown that tumor-specific CD8 + T cells are inhibited in melanoma patients through HVEM/BTLA signaling [ 28 ].…”

HVEM is a Novel Immune Checkpoint for Prostate Cancer Immunotherapy in Humanized Mice

“…Likewise, up regulated expression of BTLA on CD8 + or CD4 + T cells or increased levels of soluble BTLA were associated to unfavorable prognosis for gallbladder cancer [23], diffuse large-B cell lymphoma [24], clear cell renal cell cancer [24] and prostate cancer patients [20]. Moreover, we have shown that tumor-specific CD8 + T cells are inhibited in melanoma patients through HVEM/BTLA signaling [25].…”

“…Although the role of HVEM on T cell activation is well established, much less is known on the role of HVEM expressed by tumor cells on the immune system. Several clinical studies have shown that HVEM expression is up regulated in many types of cancers including colorectal cancers [13], melanomas [14], esophageal carcinomas [15], gastric cancers [16], hepatocarcinomas [17], breast cancers [18], lymphomas [19] or PCa [20]. In these studies, high levels of HVEM expression by tumors or soluble HVEM in the sera were associated with a worse prognosis and lower survival.…”