title: Central role of leukemia-derived factors in the development of leukemia-associated immune dysfunction.
abstract: BACKGROUND
  The underlying mechanism of tumor-associated T-cell dysfunction has been suggested to be due to an acquired abnormality in the T-cell receptor signaling complex, however, tumor-derived inhibitory factors acting on immune effectors could also explain the observed immunosuppression. Here, in a murine acute leukemia model, responses (proliferation and IL-2 secretion) to mitogens were suppressed in the early stages of leukemic progression due to a leukemia-derived soluble factor(s).
  
  
  METHODS
  Correlations between the development of immunosuppression and changes in expression of TCR signaling proteins (CD3-zeta, p56(lck), p59(fyn)), calcium mobilization, and total tyrosine kinase activity following TCR stimulation were examined.
  
  
  RESULTS
  In contrast to reduced responses to mitogens seen as early as 1 week following injection of leukemic cells, signaling abnormalities were only seen in advanced disease (ie four weeks). The only significant alteration in signaling protein expression was loss of CD3-zeta for four weeks following the initiation of leukemia. Importantly, a direct role of a leukemia-derived soluble factor(s) in the loss of CD3-zeta could be shown in vitro by co-culturing splenocytes with leukemic cells separated by a transwell for seven to 10 days. Further studies demonstrated that the leukemia-derived factor(s) stimulated splenic macrophages to secrete a second soluble factor(s) that caused the loss of CD3-zeta.
  
  
  CONCLUSIONS
  These data indicate that soluble leukemia-derived factor(s) have both immediate immunosuppressive actions and a later effect acting indirectly to induce intrinsic defects in T-cell signaling pathways via accessory cells. In some tumors, there is evidence that the soluble factor is Fas-ligand, which induces apoptosis in tumor-infiltrating T cells and the action of activated caspases cleave CD3-zeta. In this model, the soluble factor prevents apoptosis indicating a second mechanism is responsible for the loss of T-cell signaling proteins.
authors.affiliation: Department of Haematology, Guy's, King's and St. Thomas' School of Medicine, Rayne Institute, 123 Coldharbour Lane, London SE5 9NU, UK.
authors.forename: W
authors.initials: W
authors.lastname: Hirst
authors.forename: A
authors.initials: A
authors.lastname: Buggins
authors.forename: G
authors.initials: G
authors.lastname: Mufti
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001685:Biological Factors / Q000378:metabolism; D017252:CD3 Complex / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D005260:Female; D007154:Immune System Diseases / Q000378:metabolism* / Q000473:pathology; D007108:Immune Tolerance / Q000187:drug effects; D007938:Leukemia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000637:transplantation
chemical_list: D001685:Biological Factors; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D016177:Macrophage-1 Antigen