Central role of leukemia-derived factors in the development of leukemia-associated immune dysfunction

The Hematology Journal : the Official Journal of the European Haematology Association
W J HirstG Mufti

Abstract

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). 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. 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 ...Continue Reading

Citations

Sep 3, 2004·Nature Reviews. Immunology·Michal Baniyash
May 17, 2005·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Theresia M WestersArjan A van de Loosdrecht
Mar 7, 2020·British Journal of Haematology·Eleni E LadikouAndrea Gs Pepper

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