title: The expression of cytotoxic mediators is altered in mononuclear cells of patients with melanoma and increased by interferon-alpha treatment.
abstract: BACKGROUND
  The role of cytotoxic cells in the control of cancer is now well established.
  
  
  OBJECTIVE
  To evaluate the expression of perforin and granzyme A in cytotoxic cells of patients with melanoma and to look for a link between this expression and natural tumour progression; to check if interferon (IFN)-alpha administration increased expression of cytotoxic mediators; and to evaluate if this increase was correlated with the antitumoral effect of IFN-alpha.
  
  
  METHODS
  To determine in patients with melanoma the expression of the cytotoxic mediators perforin and granzyme A in peripheral blood natural killer (NK) and T cells, we used flow cytometry before and after IFN-alpha administration.
  
  
  RESULTS
  Compared with healthy volunteers, we observed in 82 patients a low percentage of NK cells harbouring perforin [75% (95% confidence interval (CI) 70-79) vs. 92% (95% CI 89-95), P < 0.001] and granzyme A [48% (95% CI 41-55) vs. 73% (95% CI 66-81), P < 0.001]. By contrast, a high percentage of T cells, and particularly of CD56+ T cells, expressed perforin [56% (95% CI 41-71) vs. 28% (95% CI 18-38), P < 0.001], whereas a low percentage of CD56+ T cells expressed granzyme A [30% (95% CI 24-36) vs. 54% (95% CI 43-65), P < 0.001]. In untreated patients, the percentage of CD56+ T cells expressing granzyme A was higher in progressors than in nonprogressors [49% (95% CI 39-58) vs. 16% (95% CI 0-33), P = 0.003]. We followed cytotoxic mediator expression in 17 patients treated with IFN-alpha. IFN-alpha administration increased granzyme A expression in NK cells [44% (95% CI 27-61) and 65% (95% CI 54-76) before and after treatment, respectively, P = 0.010], rather than perforin expression, whereas expression of both perforin [46% (95% CI 30-62), and 58% (95% CI 44-73), P = 0.112] and especially granzyme A [27% (95% CI 14-40) vs. 45% (95% CI 26-64), P = 0.016] was increased in CD56+ T cells after IFN-alpha administration. Yet, this effect was not correlated with the clinical response to IFN-alpha.
  
  
  CONCLUSIONS
  Thus, the expression of cytotoxic mediators is altered in cytotoxic cells of patients with melanoma, and increased under IFN-alpha administration.
authors.affiliation: Service de Dermatologie and Laboratoire d'Immunologie, Hôpital Saint Eloi, 2 avenue Bertin Sans, F 34.295, Montpellier Cedex 01, France. b-guillot@chu-montpelier.fr
authors.forename: B
authors.initials: B
authors.lastname: Guillot
authors.forename: P
authors.initials: P
authors.lastname: Portalès
authors.forename: A Du
authors.initials: AD
authors.lastname: Thanh
authors.forename: S
authors.initials: S
authors.lastname: Merlet
authors.forename: O
authors.initials: O
authors.lastname: Dereure
authors.forename: J
authors.initials: J
authors.lastname: Clot
authors.forename: P
authors.initials: P
authors.lastname: Corbeau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019002:CD56 Antigen / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D053804:Granzymes; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000032:analysis*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000032:analysis*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019002:CD56 Antigen; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human