CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression

Tarafdar, A. et al. (2017) CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression. Blood, 129(2), pp. 199-208. (doi:10.1182/blood-2016-09-742049) (PMID:27793879) (PMCID:PMC5305055)

[img]
Preview
Text
130643.pdf - Accepted Version

3MB

Abstract

Targeting the fusion oncoprotein BCR-ABL with tyrosine kinase inhibitors has significantly impacted on chronic myeloid leukemia (CML) treatment, transforming the life expectancy of patients; however the risk of 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 MHC-II and its master regulator class II transactivator (CIITA) are downregulated in CML compared to non-CML stem/progenitor cells in a BCR-ABL kinase independent manner. IFNγ stimulation resulted in an upregulation of CIITA and MHC-II in CML stem/progenitor cells, however the extent of IFNγ-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 (MLRs) revealed that exposure of CD34+ CML cells to IFNγ 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.

Item Type:Articles
Additional Information:Paper acknowledgements: "This study was funded by project grants from Leuka and Tenovus-Scotland (Ref. S12/21). This study was supported by the Glasgow Experimental Cancer Medicine Centre, which is funded by Cancer Research UK and the Chief Scientist’s Office, Scotland. Cell sorting facilities were funded by the Kay Kendall Leukaemia Fund (KKL501) and the Howat Foundation. A.T. was funded by a Bloodwise project grant (13012), P.G. was funded by a Medical Research Council (MRC) UK clinical research training fellowship grant (G1000288), H.G.J. was funded by the Friends of Paul O’Gorman Leukemia Research Centre, F.P., L.H. and T.L.H. were supported by Cancer Research UK Programme grant (C11074/A11008), D.V. by LLR project grant (14005) and A.M.M was supported by an MRC project grant (MR/K014854/1).”
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michie, Dr Alison and Holyoake, Professor Tessa and Vetrie, Professor David and Jorgensen, Dr Heather and Hair, Dr Alan and Tarafdar, Ms Anuradha and Pellicano, Dr Francesca and Korfi, Mr Koorosh and Hopcroft, Dr Lisa and Cassels, Miss Jennifer
Authors: Tarafdar, A., Hopcroft, L. E.M., Gallipolli, P., Pellicano, F., Cassels, J., Hair, A., Korfi, K., Jørgensen, H. G., Vetrie, D., Holyoake, T. L., and Michie, A. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:28 October 2016
Copyright Holders:Copyright © 2016 American Society of Hematology
First Published:First published in Blood 129(2):199-208
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
600561MICA: Determining the therapeutic potential of targeting mTORC-1/2 in chronic lymphocytic leukaemia - a pre-clinical studyAlison MichieMedical Research Council (MRC)MR/K014854/1ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES
591941Regulation of PKC-beta gene expression in in CLL cells.Alison MichieBloodwise (BLOODWIS)13012ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
540351The relevance of autocrine growth factor activation to the survival and proliferation of primitive chronic myeloid leukaemia (CML) cells.Paolo GallipoliMedical Research Council (MRC)G1000288RI CANCER SCIENCES
498552Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES