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

Abstract

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)-β is essential for the formation of a microenvironment supporting leukemic growth. Here we describe the effect of Idelalisib on the PKCβ/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 PKCβ 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.

Keywords:

• Idelalisib
• CLL
• stromal cells
• PKCβ
• NF-κB
• Notch

Acknowledgements

The present work was performed in fulfillment of the requirements for obtaining the degree “Dr. med.” The project was supported by the Deutsche Forschungsgemeinschaft (DFG) – Project number LU2181/1-1 and by GILEAD (Förderprogramm Onkologie). We acknowledge the kind assistance of the University of Cambridge, UK for providing blood samples from patients (MTA). The CRISPR vector was designed by David Feldser. Cell sorting and immunofluorescence analysis has been performed at the Core Units “Cell Sorting and Immunomonitoring” and the “Optical Imaging Center” Erlangen.

Author contributions

S.H.: Collection and analysis of data, manuscript writing. F.v.H.: Collection and assembly of data. S.V.: Provision of patient material. R.A.J.O.: Provision of study material. J.W.: Provision of patient material. A.N.K.: interpretation of data and final approval of the manuscript. A.M.: Administrative support, final approval of manuscript and financial support. G.L-G.: Conception and design, financial support, interpretation of data and the manuscript writing.

Table 1. Antibody list.

Table 2: Primer.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The project of G.L-G. was funded by GILEAD [Föderprogramm Onkologie].