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Inactivation of Notch signaling leads to a defective dendritic cell differentiation in cancer

Notch receptors/transcription regulators play an important role in the fate decision for hematopoietic progenitor cells (HPC). Previously we and others have demonstrated that Notch signaling may play a critical role in the development of dendritic cells (DC). Here we report that Notch signaling is involved in the abnormal differentiation of DC during tumor progression. We have found that Notch signaling (evaluated by the activity of CBF1 transcription factor and the expression of down stream targets Hes1 and Hes5) was dramatically reduced in HPC isolated from tumor‐bearing mice. The downregulation of Notch signaling in HPC caused defective differentiation of DC. Treatment of HPC or tumor‐bearing mice with Stat3 inhibitor JSI‐124 significantly increased Hes1 expression in HPC and DC differentiation. Using macrophages from Stat3−/− mice and induced activation of Stat3 in HPC by IL‐6 we have confirmed that Stat3 negatively regulated Notch signaling. Thus, our data suggest that tumor associated factors inactivate Notch signaling in HPC, leading to abnormal DC differentiation through Stat3 upregulation.