The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia

Abstract

For patients with hematologic malignancies, allogeneic hematopoietic cell transplantation (alloHCT) offers a potential curative treatment option, primarily due to an allogeneic immune response against recipient tumor cells (ie, graft-versus-leukemia [GVL] activity). However, many recipients of alloHCT develop graft-versus-host disease (GVHD), in which allogeneic immune responses lead to the damage of healthy tissue. GVHD is a leading cause of nonrelapse mortality and a key contributor to morbidity among patients undergoing alloHCT. Therefore, improving alloHCT outcomes will require treatment strategies that prevent or mitigate GVHD without disrupting GVL activity. Janus kinases (JAKs) are intracellular signaling molecules that are well positioned to regulate GVHD. A variety of cytokines that signal through the JAK signaling pathways play a role in regulating the development, proliferation, and activation of several immune cell types important for GVHD pathogenesis, including dendritic cells, macrophages, T cells, B cells, and neutrophils. Importantly, despite JAK regulation of GVHD, preclinical evidence suggests that JAK inhibition preserves GVL activity. Here we provide an overview of potential roles for JAK signaling in the pathogenesis of acute and chronic GVHD as well as effects on GVL activity. We also review preclinical and clinical results with JAK inhibitors in acute and chronic GVHD settings, with added focus on those actively being evaluated in patients with acute and chronic GVHD.

Keywords: Graft-versus-host disease; Hematopoietic cell transplantation; Janus kinase.

Figure 1. JAK Activity in aGVHD

(A) The conditioning regimen may cause the release of inflammatory cytokines (6), which signal through JAKs to activate APCs (29, 38, 39); activated macrophages migrate toward CXCL9 secreted from lymph nodes in a JAK1/JAK2-dependent process (29). (B) After HCT, JAKs regulate allogenic donor T-cell activation through secondary signals in APCs, such as CD80/86 (40), IDO, and IFN signaling (40), and in T cells downstream of the γ-chain cytokine receptor (9, 41). JAK activity in CD4⁺ and CD8⁺ T cells also promotes proliferation, whereas JAK signaling inhibits proliferation of Tregs (23). (C) After T-cell activation, migration out of the secondary lymphoid tissue is regulated by chemokine receptors, which are in turn regulated by JAK signaling (, , –47). T-cell cytotoxic activity, including GB production, is promoted by JAK activity (23, 26). Neutrophils, which may participate in GVHD (48), use JAK signaling pathways to regulate their development and activity (49). APC, antigen-presenting cell; CD, cluster of differentiation; cGVHD, chronic graft-versus-host disease; DAMP, damage-associated molecular pattern; GB, granzyme B; GVHD, graft-versus-host disease; HCT, hematopoietic stem cell transplant; IDO, indoleamine 2,3 dioxygenase; IFN, interferon; IL, interleukin; JAK, Janus kinase; JAK1/2, ambiguous role based on JAK1/JAK2 inhibition; JAK1/3, ambiguous role based on JAK1/JAK3 inhibition; MHC, major histocompatibility complex; PAMP, pathogen-associated molecular pattern; PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand 1; TCR, T-cell receptor; Treg, regulatory T cell.