title: CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression.
abstract: Targeting the fusion oncoprotein BCR-ABL with tyrosine kinase inhibitors has significantly affected chronic myeloid leukemia (CML) treatment, transforming the life expectancy of patients; however the risk for relapse remains, due to persistence of leukemic stem cells (LSCs). Therefore it is imperative to explore the mechanisms that result in LSC survival and develop new therapeutic approaches. We now show that major histocompatibility complex (MHC)-II and its master regulator class II transactivator (CIITA) are downregulated in CML compared with non-CML stem/progenitor cells in a BCR-ABL kinase-independent manner. Interferon γ (IFN-γ) stimulation resulted in an upregulation of CIITA and MHC-II in CML stem/progenitor cells; however, the extent of IFN-γ-induced MHC-II upregulation was significantly lower than when compared with non-CML CD34+cells. Interestingly, the expression levels of CIITA and MHC-II significantly increased when CML stem/progenitor cells were treated with the JAK1/2 inhibitor ruxolitinib (RUX). Moreover, mixed lymphocyte reactions revealed that exposure of CD34+CML cells to IFN-γ or RUX significantly enhanced proliferation of the responder CD4+CD69+T cells. Taken together, these data suggest that cytokine-driven JAK-mediated signals, provided by CML cells and/or the microenvironment, antagonize MHC-II expression, highlighting the potential for developing novel immunomodulatory-based therapies to enable host-mediated immunity to assist in the detection and eradication of CML stem/progenitor cells.
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: Anuradha
authors: 0000-0003-2580-9394
authors: A
authors: Tarafdar
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: Lisa E M
authors: 0000-0002-7022-1322
authors: LE
authors: Hopcroft
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.|Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, United Kingdom.
authors: Paolo
authors: 0000-0001-7254-2253
authors: P
authors: Gallipoli
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: Francesca
authors: F
authors: Pellicano
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: Jennifer
authors: J
authors: Cassels
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: Alan
authors: A
authors: Hair
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: Koorosh
authors: K
authors: Korfi
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: Heather G
authors: HG
authors: Jørgensen
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: David
authors: D
authors: Vetrie
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: Tessa L
authors: 0000-0002-0608-6066
authors: TL
authors: Holyoake
authors: Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors: Alison M
authors: 0000-0002-5404-475X
authors: AM
authors: Michie
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D016207:Cytokines; D000949:Histocompatibility Antigens Class II