Progression of benign prostatic hyperplasia is associated with pro-inflammatory mediators and chronic activation of prostate-infiltrating lymphocytes

// Melissa M. Norstrom 1, * , Emelie Radestad 2, * , Berit Sundberg 2 , Jonas Mattsson 2, 3 , Lars Henningsohn 4 , Victor Levitsky 5, 8 , Michael Uhlin 2, 3, 6, 7 1 Pharmaceutical Sciences (PS), Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland 2 Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden 3 Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Huddinge, Sweden 4 Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden 5 Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center, Zurich, Switzerland 6 Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden 7 Department of Applied Physics, Royal Institute of Technology, Stockholm, Sweden 8 Current address: Oncology Research, Molecular Partners AG, Zurich, Switzerland * These authors have contributed equally to this work Correspondence to: Emelie Radestad, e-mail: emelie.radestad@ki.se Keywords: benign prostatic hyperplasia, prostate-infiltrating lymphocytes, immunophenotyping, cytokine/chemokine profiling, inflammation Received: December 03, 2015     Accepted: February 28, 2016     Published: March 14, 2016 ABSTRACT Benign prostatic hyperplasia (BPH) is a common chronic non-malignant condition whose prevalence substantially increases with age. Immune cell infiltration and pro-inflammatory mediators have been implicated in the pathogenesis. Here, we characterized 21 extracellular markers on prostate-infiltrating lymphocytes (PILs) and analyzed expression of 26 soluble proteins in prostate tissue obtained from BPH patients ( n = 31). These data were correlated with clinical parameters and compared with peripheral blood mononuclear cells (PBMCs) ( n = 10). Increased frequencies of T cells expressing co-inhibitory receptors LAG-3, PD-1, TIM-3 or CTLA-4, and co-stimulatory receptors CD28, OX40 or 4-1BB were observed in BPH tissue compared to PBMCs. These findings are consistent with chronic activation and possible functional exhaustion of PILs that may be further augmented by several identified pro-inflammatory factors, such as IL-8 and MCP-1, promoting inflammation and chemotaxis of immune cells to the prostate. Prostate size and plasma prostate-specific antigen levels positively correlated with IL-8 and MCP-1 concentrations, and frequencies of T cells expressing CTLA-4 and TIM-3. It remains to be established whether the link between inflammation and BPH progression supported by our findings reflects a progressive failure of the immune system leading to decreased immune surveillance and development of prostate cancer.