Abstract
Abstract Ibrutinib, a Btk and Itk inhibitor, treats hematological malignancies by acting on lymphoid cells. Additionally, its efficacy against myeloid cell-mediated inflammatory diseases suggests that Ibrutinib could target myeloid cells. Previous studies show that Btk is expressed by murine dendritic cells (DCs). Further, Btk deficient DCs are more mature, express higher levels of MHC-II, co-stimulatory molecules and cytokines and thereby enhance CD4+ T cell activation. Hence, we studied the effect of Ibrutinib on DC function by treating murine bone marrow derived DCs with Ibrutinib during their development. We observed that Ibrutinib-treated DCs upregulate the expressions of MHC-II and co-stimulatory molecules such as CD80 and CD40. Further, Ibrutinib-treated DCs differentially regulate cytokine synthesis by producing more IL-10 while reducing IL-12 production. Ibrutinib-treated DCs promote CD4+ T cell proliferation and enhance T cell derived IFN-γ production. We studied the mechanism by which Ibrutinib promotes DC maturation by studying the expression of cytokines that direct DC maturation. We identified that Ibrutinib-treated DC cultures increase the induction of IFN-α and IFN-β which are known to promote DC maturation and IRF-7, a transcription factor which is expressed upon IFN-α/β activation. Hence, Ibrutinib treatment enhances DC maturation in an IFN-α/β dependent manner and should be further explored in the development of DC-based therapeutic vaccines against cancer.
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