Acquired STAT4 deficiency as a consequence of cancer chemotherapy
Cette étude suggère que, chez les patients traités pour un lymphome, l'observation de faibles niveaux de STAT4, un facteur de transcription activant notamment la production d'interféron gamma, est un effet de la chimiothérapie
Signal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is activated by IL-12 signaling and promotes Th1 cell differentiation and interferon (IFN)-γ production. Defective IFN-γ production due to STAT4 mRNA and protein deficiency occurs after autologous stem cell transplantation for lymphoma. The mechanisms of STAT4 deficiency in lymphoma patients were investigated. The tumor-bearing state is not responsible, as STAT4 levels were not significantly different in peripheral blood mononuclear cells (PBMCs) obtained from healthy control subjects versus lymphoma patients before treatment. STAT4 protein levels were significantly decreased in PBMCs and T cells obtained from lymphoma patients after standard dose chemotherapy. Furthermore, treatment of normal PBMC cultures or a natural killer (NK) cell line with chemotherapy drugs in vitro also resulted in reduced STAT4 protein and diminished IL-12-induced IFN-γ production. Translation of STAT4 protein was not impaired in chemotherapy-treated cells, whereas STAT4 protein half-life was significantly reduced. Chemotherapy drugs promoted the ubiquitination and proteasomal degradation of STAT4. Treatment with the proteasome inhibitor bortezomib reversed chemotherapy-induced STAT4 deficiency and defective IFN-γ production. Thus, acquired STAT4 deficiency in lymphoma patients is a consequence of treatment with chemotherapy. These results have important implications for design of optimal immunotherapy for lymphoma.