JAK inhibition impairs NK cell function in myeloproliferative neoplasms

K Schönberg, J Rudolph, M Vonnahme… - Cancer research, 2015 - AACR
K Schönberg, J Rudolph, M Vonnahme, S Parampalli Yajnanarayana, I Cornez, M Hejazi…
Cancer research, 2015AACR
Ruxolitinib is a small-molecule inhibitor of the JAK kinases, which has been approved for the
treatment of myelofibrosis, a rare myeloproliferative neoplasm (MPN), but clinical trials are
also being conducted in inflammatory-driven solid tumors. Increased infection rates have
been reported in ruxolitinib-treated patients, and natural killer (NK) cells are immune effector
cells known to eliminate both virus-infected and malignant cells. On this basis, we sought to
compare the effects of JAK inhibition on human NK cells in a cohort of 28 MPN patients with …
Abstract
Ruxolitinib is a small-molecule inhibitor of the JAK kinases, which has been approved for the treatment of myelofibrosis, a rare myeloproliferative neoplasm (MPN), but clinical trials are also being conducted in inflammatory-driven solid tumors. Increased infection rates have been reported in ruxolitinib-treated patients, and natural killer (NK) cells are immune effector cells known to eliminate both virus-infected and malignant cells. On this basis, we sought to compare the effects of JAK inhibition on human NK cells in a cohort of 28 MPN patients with or without ruxolitinib treatment and 24 healthy individuals. NK cell analyses included cell frequency, receptor expression, proliferation, immune synapse formation, and cytokine signaling. We found a reduction in NK cell numbers in ruxolitinib-treated patients that was linked to the appearance of clinically relevant infections. This reduction was likely due to impaired maturation of NK cells, as reflected by an increased ratio in immature to mature NK cells. Notably, the endogenous functional defect of NK cells in MPN was further aggravated by ruxolitinib treatment. In vitro data paralleled these in vivo results, showing a reduction in cytokine-induced NK cell activation. Further, reduced killing activity was associated with an impaired capacity to form lytic synapses with NK target cells. Taken together, our findings offer compelling evidence that ruxolitinib impairs NK cell function in MPN patients, offering an explanation for increased infection rates and possible long-term side effects associated with ruxolitinib treatment. Cancer Res; 75(11); 2187–99. ©2015 AACR.
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