Immunological Consequences of JAK Inhibition: Friend or Foe?

Abstract

Over the last decade, unparalleled advances have been made within the field of 'Philadelphia chromosome'-negative myeloproliferative neoplasms (MPN) regarding both disease pathogenesis and therapeutic targeting. The discovery of deregulated JAK-STAT signalling in MPN led to the rapid development of JAK inhibitor agents, targeting both mutated and wild-type JAK, which have significantly altered the therapeutic paradigm for patients with MPN. Although the largest population treated with these agents incorporates those with myelofibrosis, increasing data supports potential usage in other MPNs such as essential thromocythaemia and polycythaemia vera. Many MPNs are associated with a hyperinflammatory state and deregulation of immune homeostasis. Over the last few years, research has focused on attempting to decipher the complex and context-dependent changes that contribute to this immune deregulation. Moreover, very recent studies have demonstrated significant JAK inhibitor-mediated effects within the T cell, natural killer cell and dendritic cell compartments following exposure to JAK inhibitors. In parallel, case reports of infections occurring following exposure to ruxolitinib, many of which are atypical, have focused research efforts on delineating JAK inhibitor-associated immunological consequences. Within this review article, we will describe what is currently known about MPN-associated immune deregulation and JAK inhibitor-mediated immunomodulation.

JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression

“…This discrepancy can be interpreted as the result of a higher cell turnover in early tumorigenesis or by a tumor‐compensatory mechanism upon JAK1/2 inhibition present at early tumor stages. In agreement with previous reports, ruxolitinib treatment diminished tumor infiltrating CD8 + and CD4 + T cells and significantly lowered NK cell numbers but did not result in tumor metastasis, even in the absence of p53 . In agreement with others, JAK inhibition abrogated interferon‐γ‐mediated STAT1 signaling and reduced PD‐L1 expression levels .…”

“…These data suggests that ruxolitinib impairs the progression of established K‐RAS‐driven lung AC. Since JAK signaling plays a crucial role in regulating the immune system, we analyzed if JAK1/2 inhibition affected the composition of the TME by performing flow cytometric analysis of lung tumors . Indeed, the abundance of tumor promoting granulocytic CD45 + CD11b + LY6G + and monocytic CD45 + CD11b + LY6C + MDSC was significantly reduced in the lungs of tumor‐bearing, ruxolitinib‐treated mice.…”

“…In addition to these tumor‐cell intrinsic effects, JAK signaling is also substantially involved in shaping the tumor microenvironment (TME) by modulating T, natural killer (NK) and dendritic cell functions . As in tumor cells, JAK activation in the TME and its role in tumorigenesis is controversially discussed.…”

Reactivation of Pulmonary Tuberculosis following Treatment of Myelofibrosis with Ruxolitinib

“…TNF- α plays a crucial role in T cell function, macrophage activation, and granuloma formation. This poses a threat for reactivation or dissemination of infections, particularly atypical bacterial, mycobacterial, fungal, and viral infections [17]. …”

Resolution of thrombocytopenia, but not polycythemia after ruxolitinib for polycythemia vera with detectable mutation in the exon 12 of the JAK2 gene

“…It was found that patients with immune thrombocytopenia have an increased Th17 population and defective function of regulatory T cells (Tregs) [5]. The recent data show that treatment with ruxolitinib resulted in a significant reduction of regulatory Tregs and polarization of CD4+ cells from a Th1 to a Th17 phenotype [6]. In this context, ruxolitinib treatment should rather deepen thrombocytopenia than improve it.…”