title: Dysregulated expression of both the costimulatory CD28 and inhibitory CTLA-4 molecules in PB T cells of advanced cervical cancer patients suggests systemic immunosuppression related to disease progression.
abstract: Cervical cancer (CC) occurs more frequently in women who are immunosuppressed, suggesting that both local and systemic immune abnormalities may be involved in the evolution of the disease. Costimulatory CD28 and inhibitory CTLA-4 molecules expressed in T cells play a key role in the balanced immune responses. There has been demonstrated a relation between CD28, CTLA-4, and IFN genes in susceptibility to CC, suggesting their importance in CC development. Therefore, we assessed the pattern of CD28 and CTLA-4 expression in T cells from PB of CC patients with advanced CC (stages III and IV according to FIGO) compared to controls. We also examined the ability of PBMCs to secrete IFN-gamma. We found lower frequencies of freshly isolated and ex vivo stimulated CD4 + CD28+ and CD8 + CD28+ T cells in CC patients than in controls. Loss of CD28 expression was more pronounced in the CD8+ T subset. Markedly increased proportions of CTLA-4+ T cells in CC patients before and after culture compared to controls were also observed. In addition, patients' T cells exhibited abnormal kinetics of surface CTLA-4 expression, with the peak at 24 h of stimulation, which was in contrast to corresponding normal T cells, revealing maximum CTLA-4 expression at 72 h of stimulation. Of note, markedly higher IFN-gamma concentrations were shown in supernatants of stimulated PBMCs from CC patients.
  
  
  CONCLUSIONS
  Our report shows the dysregulated CD28 and CTLA-4 expression in PB T cells of CC patients, which may lead to impaired function of these lymphocytes and systemic immunosuppression related to disease progression.
authors.affiliation: Department of Experimental Therapy, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114, Wroclaw, Poland. kosmacz@iitd.pan.wroc.pl
authors.forename: Agata
authors.initials: A
authors.lastname: Kosmaczewska
authors.forename: Dorota
authors.initials: D
authors.lastname: Bocko
authors.forename: Lidia
authors.initials: L
authors.lastname: Ciszak
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska-Polinska
authors.forename: Jan
authors.initials: J
authors.lastname: Kornafel
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Szteblich
authors.forename: Anna
authors.initials: A
authors.lastname: Masternak
authors.forename: Irena
authors.initials: I
authors.lastname: Frydecka
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D008875:Middle Aged; D011379:Prognosis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007371:Interferon-gamma
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