JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells

Summary CD 4 + T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms ( MPN ), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors ( JAK i) results in improvements in MPN ‐associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAK i on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD 4 + T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD 4 + CD 127 low CD 25 high FOXP 3 + T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAK i therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)‐17 cells increased. We also describe a functional ‘silencing’ of T helper cells both in vivo and in vitro and a blockade of pro‐inflammatory cytokines from these cells. This profound effect of JAK i on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs.