Effect of Ibrutinib on the IFN Response of Chronic Lymphocytic Leukemia Cells.

Effect of Ibrutinib on the IFN Response of Chronic Lymphocytic Leukemia Cells.
J Immunol. 2020 Oct 16;:
Authors: Xia M, Luo TY, Shi Y, Wang G, Tsui H, Harari D, Spaner DE
Abstract
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has profound activity in chronic lymphocytic leukemia (CLL) but limited curative potential by itself. Residual signaling pathways that maintain survival of CLL cells might be targeted to improve ibrutinib's therapeutic activity, but the nature of these pathways is unclear. Ongoing activation of IFN receptors in patients on ibrutinib was suggested by the presence of type I and II IFN in blood together with the cycling behavior of IFN-stimulated gene (ISG) products when IFN signaling was blocked intermittently with the JAK inhibitor ruxolitinib. IFN signaling in CLL cells from human patients was not prevented by ibrutinib in vitro or in vivo, but ISG expression was significantly attenuated in vitro. ISGs such as CXCL10 that require concomitant activation of NF-κB were decreased when this pathway was inhibited by ibrutinib. Other ISGs, exemplified by LAG3, were decreased as a result of inhibited protein translation. Effects of IFN on survival remained intact as type I and II IFN-protected CLL cells from ibrutinib in vitro, which could be prevented by ruxolitinib and IFNR blocking Abs. These observations suggest that IFNs may help CLL cells persist and specific targeting of IFN signaling might deepen clini...

Source: Journal of Immunology - October 16, 2020 Category: Allergy & Immunology Authors: Xia M, Luo TY, Shi Y, Wang G, Tsui H, Harari D, Spaner DE Tags: J Immunol Source Type: research