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Current Hematologic Malignancy Reports
Published in: Current Hematologic Malignancy Reports 4/2015

01-12-2015 | Myeloproliferative Disorders (C Harrison, Section Editor)

Immunological Consequences of JAK Inhibition: Friend or Foe?

Authors: Donal P. McLornan, Alesia A. Khan, Claire N. Harrison

Published in: Current Hematologic Malignancy Reports | Issue 4/2015

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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.
Literature
1.
James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature. 2005;434(7037):1144–8.CrossRefPubMed
2.
Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):779–90.CrossRef
3.
Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387–97.CrossRefPubMed
4.
Baxter EJ, Scott LM, Campbell PJ, et al. Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–61. Erratum in: Lancet 2005; 366(9480)122.CrossRefPubMed
5.
Quintas-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115:3109–17.PubMedCentralCrossRefPubMed
6.
7.
Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24:1128–38.PubMedCentralCrossRefPubMed
8.
Larsen TS, Christensen JH, Hasselbalch HC, Pallisgaard N. The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders. Br J Haematol. 2007;136(5):745–51.CrossRefPubMed
9.
Delhommeau F, Dupont S, Tonetti C, et al. Evidence that the JAK2 G1849T (V617F) mutation occurs in a lympho-myeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood. 2006;109:71–7.CrossRefPubMed
10.
11.
12.••
Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787–98. COMFORT-II trial. CrossRefPubMed
13.••
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807. COMFORT-I trial. CrossRefPubMed
14.
Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426–35.PubMedCentralCrossRefPubMed
15.
Eghtedar A, Verstovsek S, Estrov Z, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012;119:4614–8.PubMedCentralCrossRefPubMed
16.
Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol. 2012;167(3):668–77.CrossRefPubMed
17.
18.
Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377–86.CrossRefPubMed
19.
Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel Janus kinase 1,2 inhibitor. Chest. 2013;143:1478–9.CrossRefPubMed
20.
Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med. 2013;369:681–3.CrossRefPubMed
21.
Caocci G, Murgia F, Podda L, Solinas A, Atzeni S, La Nasa G. Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia. 2014;28:225–7.CrossRefPubMed
22.
Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med. 2013;369:197–8.CrossRefPubMed
23.
24.
25.
Müller M, Briscoe J, Laxton C, et al. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993;366(6451):129–35.CrossRefPubMed
26.
Schindler C, Levy D, Decker T. JAK-STAT signaling: from interferons to cytokines. J Biol Chem. 2007;282(28):20059–63.CrossRefPubMed
27.
Krishnan K, Pine R, Krolewski JJ. Kinase-deficient forms of Jak1 and Tyk2 inhibit interferon signaling in a dominant manner. Eur J Biochem. 1997;247:298–305.CrossRefPubMed
28.
O’Sullivan LA, Liongue C, Lewis RS, Stephenson SE, Ward AC. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol. 2007;44(10):2497–506.CrossRefPubMed
29.
30.
Macchi P, Villa A, Giliani S, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995;377:65.CrossRefPubMed
31.
Ishizaki M, Akimoto T, Muromoto R, et al. Involvement of tyrosine kinase-2 in both theIL-12/Th1 and IL-23/Th17 axes in vivo. J Immunol. 2011;187(1):181–9.CrossRefPubMed
32.
Tokumasa N, Suto A, Kagami S, et al. Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-gamma production and the induction of Th1 cell differentiation. Blood. 2007;110(2):553–60.CrossRefPubMed
33.
Prchal-Murphy M, Witalisz-Siepracka A, Bednarik K, et al. In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity. Oncoimmunology. 2015.
34.
Agnello D, Lankford CS, Bream J, et al. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol. 2003;23(3):147–61.CrossRefPubMed
35.
36.
Yang XO, Panopoulos AD, Nurieva R, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007;282(13):9358–63.CrossRefPubMed
37.
38.
Kristinsson SY, Landgren O, Samuelsson J, Björkholm M, Goldin LR. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica. 2010;95(7):1216–20.PubMedCentralCrossRefPubMed
39.
Barcellini W, Iurlo A, Radice T, et al. Increased prevalence of autoimmune phenomena in myelofibrosis: relationship with clinical and morphological characteristics, and with immunoregulatory cytokine patterns. Leuk Res. 2013;37(11):1509–15.CrossRefPubMed
40.
Skov V, Larsen TS, Thomassen M, et al. Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: identification of deregulated genes of significance for inflammation and immune surveillance. Leuk Res. 2012;36(11):1387–92.CrossRefPubMed
41.
Skov V, Riley CH, Thomassen M, et al. Whole blood transcriptional profiling reveals significant down-regulation of human leukocyte antigen class I and II genes in essential thrombocythemia, polycythemia vera and myelofibrosis. Leuk Lymphoma. 2013;54(10):2269–73.CrossRefPubMed
42.
Tefferi A, Vaidya R, Caramazza D, et al. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol. 2011;29(10):1356–63.CrossRefPubMed
43.
Vannucchi AM, Bianchi L, Paoletti F, et al. A pathologic pathway linking thrombopoietin, GATA-1 and TGF-β1 in the development of myelofibrosis. Blood. 2005;105(9):3493–501.CrossRefPubMed
44.
Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol. 1998;16:137–61.CrossRefPubMed
45.
Kundra A, Baptiste S, Chen C, Sindhu H and Wang JC. Programmed cell death receptor (PD-1), PD-1 ligand (PD-L1) expression and myeloid derived suppressor cells (MDSC) in myeloid neoplasms implicate the mechanism of IMiD treatment of myelofibrosis. Blood (supplement) 2013; abstract 2837.
46.
Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122:4047–53.CrossRefPubMed
47.
Wilkins BS, Radia D, Woodley C, et al. Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. Haematologica. 2013;98(12):1872–6.PubMedCentralCrossRefPubMed
48.
Lee SC, Feenstra J, Georghiou PR. Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. BMJ Case Rep. 2014. 2014.
49.
Landman GW, Arend SM, van Dissel JT. Ruxolitinib can mask symptoms and signs of necrotizing fasciitis. J Infect. 2013;66(3):296–7.CrossRefPubMed
50.
Kim Y-K, Lee SR, Park Y, et al. Efficacy of ruxolitinib in Korean myelofibrosis patients and cases complicated TB lymphadenitis during the treatment. Blood. 2013;122:1596.
51.
Mesa R, Egyed M, Szoke A et al. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin Oncol 33, 2015 (suppl; abstr LBA7006)
52.
Singer J, Al-Fayoumi S, Ma H et al. Comprehensive kinase profile of pacritinib, a non-myelosuppressive JAK2 kinase inhibitor in phase 3 development in primary and post ET/PV myelofibrosis. [abstract] 2013; Blood: 122 (21) 1874.
53.
Pardanani A, Harrison C, Cortes J et al. Results of a randomized, double-blind, placebo-controlled phase III study (JAKARTA) of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis (MF). [abstract] 2013; Blood: 122 (21) 393.
54.
Zhang Q, Zhang Y, Diamond S, et al. The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke’s encephalopathy. Drug Metab Dispos. 2014;42(10):1656–62.CrossRefPubMed
55.
Pardanani A, Gotlib J, Gupta V et al. Update on the long-term efficacy and safety of momelotinib, a JAK1 and JAK2 Iinhibitor, for the treatment of myelofibrosis. [abstract] 2013; Blood: 122 (21) 108.
56.
Verstovsek S, Mesa R, Salama M et al. Phase I study of LY2784544, a JAK2 selective inhibitor, in patients with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). [abstract] 2013; Blood: 122 (21).
57.
Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010;7:41.CrossRef
58.
Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60(7):1895–905.CrossRefPubMed
59.
Cohen S, Radominski SC, Gomez-Reino JJ, Wang L, Krishnaswami S, Wood SP, et al. Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66(11):2924–37.CrossRefPubMed
60.
Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, long term extension studies. J Rheumatol. 2014;41(5):837–52.CrossRefPubMed
61.
Vincenti F, Tedesco Silva H, Busque S, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am J Transplant : Off J Am Soc Transplant Am Soc Transplant Surg. 2012;12:2446–56.CrossRef
62.
Massa M, Rosti V, Campanelli R, Fois G, Barosi G. Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib. Leukemia. 2014;28(2):449–51.CrossRefPubMed
63.
Keohane C, Kordasti SY, Siedl T et al. JAK inhibition reduces CD25 high CD27+ FOXp3+ T regulatory cells and causes a silencing of T effector cells in patients with myeloproliferative neoplasms whilst promoting a TH17 phenotype. Abstract 4092 Blood 2013
64.
Sharma MD, Hou DY, Baban B, et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity. 2010;33(6):942–54.PubMedCentralCrossRefPubMed
65.
Parampalli Yajnanarayana S, Stübig T, Cornez I, et al. JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. Br J Haematol. 2015 [Epub ahead of print]
66.
Perner F, Saalfeld F, Schnoeder T et al. Specificity of JAK-kinase inhibition determines impact on T-cell function. [abstract] 2013; Blood: 122 (21) 1410.
67.
68.
Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22(11):633–40. Review.CrossRefPubMed
69.
Radaev S, Sun PD. Structure and function of natural killer cell surface receptors. Annu Rev Biophys Biomol Struct. 2003;32:93–114. Epub 2002. Review. 32, 93-114.CrossRefPubMed
70.
De Maria A, Bozzano F, Cantoni C, Moretta L. Revisiting human natural killer cell subset function revealed cytolytic CD56(dim)CD16+ NK cells as rapid producers of abundant IFN-gamma on activation. Proc Natl Acad Sci U S A. 2011;108(2):728–32.PubMedCentralCrossRefPubMed
71.
Fauriat C, Long EO, Ljunggren H-G, Bryceson YT. Regulation of human NK cell cytokine and chemokine production by target cell recognition. Blood. 2010;115:2167–76.PubMedCentralCrossRefPubMed
72.
Gersuk GM, Carmel R, Pattamakom S, Challita PM, Rabinowitz AP, Pattengale PK. Quantitative and functional studies of impaired natural killer (NK) cells in patients with myelofibrosis, essential thrombocythemia, and polycythemia vera. I. A potential role for platelet-derived growth factor in defective NK cytotoxicity. Nat Immun. 1993;12(3):136–51.PubMed
73.
Riley CH, Hansen M, Brimnes MK, et al. Expansion of circulating CD56bright natural killer cells in patients with JAK2-positive chronic myeloproliferative neoplasms during treatment with interferon-α. Eur J Haematol. 2015;94(3):227–34.CrossRefPubMed
74.
Schönberg K, Rudolph J, Vonnahme M et al. JAK inhibition impairs NK cell function in myeloproliferative neoplasms. Cancer Res. 2015.
75.
76.
Watowich S, Liu YJ. Mechanisms regulating dendritic cell specification and development. J Exp Med. 2003;198(2):305–13.CrossRef
77.
Li HS, Watowich SS. Diversification of dendritic cell subsets: emerging roles for STAT proteins. JAKSTAT. 2013;2(4):e25112.PubMedCentralPubMed
78.
Zhong J, Yang P, Muta K, et al. Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock. PLoS ONE. 2010;5(3):e9593.PubMedCentralCrossRefPubMed
79.
Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122(7):1192–202.CrossRefPubMed
80.
Kubo S, Yamaoka K, Kondo M, et al. The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis. 2014;73(12):2192–8.CrossRefPubMed
81.
Spoer S, Mathew N, Bscheider M et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. 2014; Blood: 123 (24).
82.
83.
Spoerl S, Maas-Bauer K, Verbeek M et al. Response to JAK 1/2 inhibition in patients with corticosteroid-refractory acute graft-versus-host disease. ASH 2014 meeting abstract
84.
Carniti C, Gimondi S, Vendramin A, et al. Pharmacologic inhibition of JAK1/JAK2 signaling reduces experimental murine acute GVHD while preserving GVT effects. Clin Cancer Res. 2015.
85.
86.
Ports WC, Khan S, Lan S, et al. A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis. Br J Dermatol. 2013;169(1):137–45.PubMedCentralCrossRefPubMed
87.
88.
Punwani N, Scherle P, Flores R, et al. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol. 2012;67(4):658–64.CrossRefPubMed
Metadata
Title
Immunological Consequences of JAK Inhibition: Friend or Foe?
Authors
Donal P. McLornan
Alesia A. Khan
Claire N. Harrison
Publication date
01-12-2015
Publisher
Springer US
Published in
Current Hematologic Malignancy Reports / Issue 4/2015
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-015-0284-z

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