Immune modulatory effects of Idelalisib in stromal cells of chronic lymphocytic leukemia.

Molecular targets of tyrosine kinase inhibitors are not restricted to the B-cell compartment but also regulate functions in the tumor microenvironment. Increasing evidence suggests that B-cell receptor-associated kinases like protein kinase C (PKC)-ß is essential for the formation of a microenvironment supporting leukemic growth. Here we describe the effect of Idelalisib on the PKCß/NF-κB and Notch pathway in stromal cells upon contact to primary chronic lymphocytic leukemia cells (CLL). There is no Idelalisib-dependent regulation of the Notch expression in stromal cells, whereas Idelalisib induces PKCß expression and activates the canonical NF-κB pathway. Idelalisib deregulates important immune-modulatory proteins in activated stromal cells, which might provoke the patient's side effects. Additionally, we established a 3D-stroma/leukemia model, that can give us a more defined look into the communication between tumor and stromal cells than standard cell cultures. This opens up the possibility to improve therapies, especially in the context of minimal-residual disease.