CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression
Tarafdar A., Hopcroft LEM., Gallipolli P., Pellicano F., Cassels J., Hair A., Korfi K., J�rgensen HG., Vetrie D., Holyoake TL., Michie AM.
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. IFN? stimulation resulted in an upregulation of CIITA and MHC-II in CML stem/progenitor cells, however the extent of IFN?-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 IFN? 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.