Abstract
Programmed cell death protein 1 (PD-1) and its ligand Programmed death ligand 1 (PD-L1) have gained massive attention in cancer research due to recent availability and their targeted antitumor effects. Their role in prostate cancer is still undetermined. We constructed tissue microarrays from prostatectomy specimens from 535 prostate cancer patients. Following validation of antibodies, immunohistochemistry was used to evaluate the expression of PD-1 in lymphocytes and PD-L1 in epithelial and stromal cells of primary tumors. PD-L1 expression was commonly seen in tumor epithelial cells (92% of cases). Univariate survival analysis revealed a positive association between a high density of PD-1+ lymphocytes and worse clinical failure-free survival, limited to a trend (p = 0.084). In subgroups known to indicate unfavorable prostate cancer prognosis (Gleason grade 9, age < 65, preoperative PSA > 10, pT3) patients with high density of PD-1+ lymphocytes had a significantly higher risk of clinical failure (p = < 0.001, p = 0.025, p = 0.039 and p = 0.011, respectively). In the multivariate analysis, high density of PD-1+ lymphocytes was a significant negative independent prognostic factor for clinical failure-free survival (HR = 2.48, CI 95% 1.12–5.48, p = 0.025).
Highlights
Prostate cancer is a major contributor to cancer burden and death among men worldwide [1, 2], and issues multiple challenges regarding diagnostics and disease management
The pathway consists of the receptor programmed cell death protein 1 and its ligands programmed death ligand 1 and programmed death ligand 2, where the former is believed to be of www.impactjournals.com/oncotarget greatest significance
At the last follow-up in December 2015, 200 patients had experienced biochemical failure (BF), 56 patients had clinical failure (CF), and 18 patients were dead of prostate cancer
Summary
Prostate cancer is a major contributor to cancer burden and death among men worldwide [1, 2], and issues multiple challenges regarding diagnostics and disease management. Multiple mechanisms have been identified, including the exploitation of natural immunosuppressive pathways such as the programmed cell death protein 1 (PD-1) pathway [5, 6]. In healthy individuals, this pathway is important for maintaining self-tolerance, as well as curbing T cells during an immune response, preventing collateral damage to healthy tissues [7]. It is proposed that malignant cells express PD-L1 through genetic mutations or epigenetic changes, and as a response to an inflammatory environment [5] This enables them to directly inactivate tumor infiltrating lymphocytes (TILs), and escaping immune destruction. In addition to activating PD-1, PD-L1 has immunomodulatory effects within the cell on which it is expressed [5]
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