title: Progression of benign prostatic hyperplasia is associated with pro-inflammatory mediators and chronic activation of prostate-infiltrating lymphocytes.
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.
authors.affiliation: Pharmaceutical Sciences (PS), Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Norström
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Rådestad
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Berit
authors.initials: B
authors.lastname: Sundberg
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.|Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Mattsson
authors.affiliation: Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Henningsohn
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center, Zurich, Switzerland.|Current address: Oncology Research, Molecular Partners AG, Zurich, Switzerland.
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.|Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Huddinge, Sweden.|Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.|Department of Applied Physics, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Uhlin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D005500:Follow-Up Studies; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011467:Prostate / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines
keywords: benign prostatic hyperplasia; cytokine/chemokine profiling; immunophenotyping; inflammation; prostate-infiltrating lymphocytes