title: Decreased expression of pSTAT, IRF-1 and DAP10 signalling molecules in peripheral blood lymphocytes of patients with metastatic melanoma.
abstract: OBJECTIVE
  As numerous signalling molecules regulate effector functions of peripheral blood lymphocytes (PBLs) that have an important anti-tumour activity, the aim of this study was to analyse their level in patients with metastatic melanoma (MM) compared with healthy controls (HCs).
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) of 36 MMs and 28 HCs were analysed for the level of perforin, interferon-regulating transcription factor-1 (IRF-1), DAP10 and Src homology 2 domain-containing tyrosine phosphatase-1 by reverse transcriptase PCR, level of phosphorylated signal transducers and activators of transcription (pSTAT)-1, pSTAT-4, pSTAT-5 by western blot and interferon (IFN)-γ production by ELISA. The expression of activating NKG2D and inhibitory killer immunoglobulin-like receptors (KIR), CD158a and CD158b, on PBL, CD3-CD56+ natural killer (NK) cells and CD3+CD8+ cytotoxic T lymphocytes (CTLs), as well as the percentage of CD14+HLA-DR- cells in PBMC were estimated by flow cytometry.
  
  
  RESULTS
  Patients with MM, compared with HCs, had significantly lower level of cytotoxic molecule perforin and decreased IFN-γ production, as well as lower level of pSTAT-1, pSTAT-4, pSTAT-5 and IRF-1 signalling molecules in PBMC. Furthermore, MM had decreased expression of activating NKG2D receptor on PBL and NK cells and low level of its DAP10 signalling molecule contrary to no changes in KIR expression on all investigated cells. These results could be associated with increased percentage of immunosuppressive CD14+HLA-DR- myeloid-derived suppressor cells detected in patients with MM.
  
  
  CONCLUSIONS
  The altered signalling molecules of PBL could represent biomarkers of impaired cytotoxic and immunoregulatory function of these cells, indicating melanoma-associated immunosuppression that facilitates tumour progression.
authors.affiliation: Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Mirjačić Martinović
authors.affiliation: Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Srdić-Rajić
authors.affiliation: Department of Medical Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia.
authors.forename: Nada
authors.initials: N
authors.lastname: Babović
authors.affiliation: Surgical Oncology Clinic, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Radan
authors.initials: R
authors.lastname: Džodić
authors.affiliation: Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Jurišić
authors.affiliation: Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Gordana
authors.initials: G
authors.lastname: Konjević
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000276:immunology; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis*; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C120528:HCST protein, human; D050856:Interferon Regulatory Factor-1; D011971:Receptors, Immunologic; D050791:STAT Transcription Factors
keywords: CELL CYCLE REGULATION; IMMUNOPHENOTYPING; MELANOMA