Mechanisms Underlying the Anti-inflammatory and Immunosuppressive Activity of Ruxolitinib

Abstract

The JAK-STAT signaling pathway plays a central role in signal transduction in hematopoietic cells, as well as in cells of the immune system. The occurrence in most patients affected by myeloproliferative neoplasms (MPNs) of driver mutations resulting in the constitutive activation of JAK2-dependent signaling identified the deregulated JAK-STAT signal transduction pathway as the major pathogenic mechanism of MPNs. It also prompted the development of targeted drugs for MPNs. Ruxolitinib is a potent and selective oral inhibitor of both JAK2 and JAK1 protein kinases. Its use in patients with myelofibrosis is associated with a substantial reduction in spleen volume, attenuation of symptoms and decreased mortality. With growing clinical experience, concerns about infectious complications, and increased risk of B-cell lymphoma, presumably caused by the effects of JAK1/2 inhibition on immune response and immunosurveillance, have been raised. Evidence shows that ruxolitinib exerts potent anti-inflammatory and immunosuppressive effects. Cellular targets of ruxolitinib include various components of both the innate and adaptive immune system, such as natural killer cells, dendritic cells, T helper, and regulatory T cells. On the other hand, immunomodulatory properties have proven beneficial in some instances, as highlighted by the successful use of ruxolitinib in corticosteroid-resistant graft vs. host disease. The objective of this article is to provide an overview of published evidence addressing the key question of the mechanisms underlying ruxolitinib-induced immunosuppression.

Keywords: JAK inhibitors; T cells; dendritic cells; immune system; immunosuppression; myeloproliferative neoplasms (MPNs); natural killer (NK) cells; ruxolitinib.

Figure 1

Distribution of the most important infectious events, regardless of relationship to study drug, in the principal studies of ruxolitinib in myelofibrosis.

Figure 2

Cellular targets of immunosuppressive activity of ruxolitinib: T helper (Th)1 cells differentiate in the presence of interleukin (IL)-12 and are committed through STAT1. Fully committed Th1 cells produce interferon (IFN)-gamma through STAT4, of key importance for cell-mediated immune responses against intracellular bacteria and viruses. Th17 cells differentiate in the presence of IL-23 and are committed through STAT3. Fully committed Th17 produce IL-17 and IL-22 through STAT3, with a principal role for cell-mediated immune responses against extracellular bacteria and fungi. Tregs, through STAT5, produce IL-10 and transforming growth factor (TGF)-beta, contributing to immunosurveillance.