Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets – Beyond B Lymphocytes

Abstract

The clinical success of the two BTK inhibitors, ibrutinib and acalabrutinib, represents a major breakthrough in the treatment of chronic lymphocytic leukemia (CLL) and has also revolutionized the treatment options for other B cell malignancies. Increasing evidence indicates that in addition to their direct effects on B lymphocytes, both BTK inhibitors also directly impact the homeostasis, phenotype and function of many other cell subsets of the immune system, which contribute to their high efficacy as well as adverse effects observed in CLL patients. In this review, we attempt to provide an overview on the overlapping and differential effects of ibrutinib and acalabrutinib on specific receptor signaling pathways in different immune cell subsets other than B cells, including T cells, NK cells, monocytes, macrophages, granulocytes, myeloid-derived suppressor cells, dendritic cells, osteoclasts, mast cells and platelets. The shared and distinct effects of ibrutinib versus acalabrutinib are mediated through BTK-dependent and BTK-independent mechanisms, respectively. Such immunomodulatory effects of the two drugs have fueled myriad explorations of their repurposing opportunities for the treatment of a wide variety of other human diseases involving immune dysregulation.

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

“…Interestingly, although ibrutinib alone has very modest effects on T-PLL cells, the combination of ibrutinib and the BCL-2 inhibitor venetoclax exhibits strong synergism at inducing 1 and 2). These clinical trials are elicited by strong preclinical evidence indicating that ibrutinib and acalabrutinib will potentially have broad applications in the treatment of various solid tumors because of their multi-layered mechanisms of action (24,28,29,53,(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79). These include both direct tumoricidal activities on cancer cells and indirect immunomodulatory effects on different immune cell subsets as well as other relevant cell types in the tumor microenvironment (TME) via on-target inhibition of BTK (for both drugs) or off-target inhibition of ITK or EGFR (for ibrutinib) (2, 24, 28, 29).…”

“…Indeed, BTK is critical for the function of multiple cell types representing important components of the TME, including macrophages, MDSCs, DCs, neutrophils, B cells and endothelial cells (2,24,28,29). In particular, BTK is overexpressed in TAMs a n d M D S C s , w h i c h r e g u l a t e t u m o r p r o g r e s s i o n , immunosuppression and angiogenesis (71,84,85).…”

“…In particular, BTK is overexpressed in TAMs a n d M D S C s , w h i c h r e g u l a t e t u m o r p r o g r e s s i o n , immunosuppression and angiogenesis (71,84,85). Ibrutinib treatment, Btk deficiency or siRNA-mediated knockdown of BTK shifts macrophage polarization from tumor-promoting M2-like macrophages toward inflammatory M1-like and diminishes PD-1 and SIRPa expression on macrophages (24,77,86,87). Ibrutinib treatment also inhibits MDSC generation, induces MDSC differentiation to mature DCs, and impairs IDO expression and NO production in MDSCs, resulting in reduced MDSC-mediated immunosuppression and increased CD8 T cell proliferation, infiltration and effector function in the TME (71,80,84,88).…”

“…Interestingly, mounting preclinical and clinical evidence indicates that both BTK inhibitors are much more versatile than initially envisioned and have direct effects on many cell types beyond B lymphocytes (24). In addition to B cells, many other cell types express BTK under physiological or pathological conditions, including T cells, monocytes, macrophages, granulocytes, myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), osteoclasts, mast cells, erythrocytes, platelets, epithelial cells, neurons and astrocytes (3,(24)(25)(26)(27)(28)(29)(30)(31).…”

“…Interestingly, mounting preclinical and clinical evidence indicates that both BTK inhibitors are much more versatile than initially envisioned and have direct effects on many cell types beyond B lymphocytes (24). In addition to B cells, many other cell types express BTK under physiological or pathological conditions, including T cells, monocytes, macrophages, granulocytes, myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), osteoclasts, mast cells, erythrocytes, platelets, epithelial cells, neurons and astrocytes (3,(24)(25)(26)(27)(28)(29)(30)(31). Most notably, both ibrutinib and acalabrutinib have complex immunomodulatory effects on various non-B immune cell subsets by inhibiting BTK-dependent signaling pathways of specific immune receptors, including T cell receptor (TCR), Toll-like receptors (TLRs), NLRP3, TREM-1, Dectin-1, CXCR4, CXCR5, RANK, Fc receptors and CLEC-2, among others (2, 3, 6, 24-26, 32, 33).…”