title: JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells.
abstract: CD4(+) 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 (JAKi) results in improvements in MPN-associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAKi on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD4(+) 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 CD4(+)  CD127(low)  CD25(high)  FOXP3(+) T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAKi 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 JAKi on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs.
authors.affiliation: Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK.|Department of Haematological Medicine, Kings College London, London, UK.
authors.forename: Clodagh
authors.initials: C
authors.lastname: Keohane
authors.affiliation: Department of Haematological Medicine, Kings College London, London, UK.|Department of Haematological Medicine, Kings College Hospital NHS Foundation Trust, London, UK.
authors.forename: Shahram
authors.initials: S
authors.lastname: Kordasti
authors.affiliation: Department of Haematological Medicine, Kings College London, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seidl
authors.affiliation: Department of Haematological Medicine, Kings College London, London, UK.
authors.forename: Pilar
authors.initials: P
authors.lastname: Perez Abellan
authors.affiliation: Department of Haematological Medicine, Kings College London, London, UK.
authors.forename: Nicholas S B
authors.initials: NS
authors.lastname: Thomas
authors.affiliation: Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Claire N
authors.initials: CN
authors.lastname: Harrison
authors.affiliation: Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK.|Department of Haematological Medicine, Kings College Hospital NHS Foundation Trust, London, UK.
authors.forename: Donal P
authors.initials: DP
authors.lastname: McLornan
authors.affiliation: Department of Haematological Medicine, Kings College London, London, UK.|Department of Haematological Medicine, Kings College Hospital NHS Foundation Trust, London, UK.
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D009570:Nitriles; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines; D011759:Pyrrolidines / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
chemical_list: D016207:Cytokines; D053612:Janus Kinases; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011759:Pyrrolidines; D013449:Sulfonamides; C528327:fedratinib; D000096926:Benzenesulfonamides; C540383:ruxolitinib
keywords: immunology; myeloproliferative disorder; therapy