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

Abstract

Key Points• MHC-II and its master regulator CIITA are downregulated in CML stem/ progenitor cells in a BCR-ABL kinase-independent manner. • JAK1/2 inhibition increased MHC-II expression, suggesting elevation of CML immunogenicity may provide a way to reduce CML persistence.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 g (IFN-g) stimulation resulted in an upregulation of CIITA and MHC-II in CML stem/progenitor cells; however, the extent of IFN-g-induced MHC-II upregulation was significantly lower than when compared with non-CML CD34 1 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 1 CML cells to IFN-g or RUX significantly enhanced proliferation of the responder CD4 1 CD69 1 T cells. Taken together, these data suggest that cytokine-driven JAKmediated 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. (Blood. 2017;129(2):199-208)

The chronic myeloid leukemia stem cell: stemming the tide of persistence

“…Blockade of the PD-1/PD-L1 interaction in combination with T-cell immunotherapy was able to trigger the loss of LSC, and prevent development of CML-like disease 96 . Our recent work has demonstrated that cytokine-mediated downregulation of MHC-II expression may be an alternative way that LSC evade immune surveillance -and treatment with ruxolitinib or interferon gamma (IFNγ) can reverse this effect in vitro and enhance proliferation of responder CD4 + CD69 + T cells in mixed lymphocyte reactions 97 . These examples represent exciting areas of research that could lead to new immune therapy-based therapeutic approaches.…”

CML Hematopoietic Stem Cells Expressing IL1RAP Can Be Targeted by Chimeric Antigen Receptor–Engineered T Cells

“…In addition to the well-known graft-versus-leukemia effect of allo-SCT, other features point to CML as an immune-sensitive disease. These characteristics include immune surveillance evasion after downregulation of MHC-II expression by CML cells (15), BCR-ABL fusion region peptides that elicit CML-specific T-cell responses (16), the potential for autologous dendritic cell vaccination, the role of natural killer (NK) cells (17), the anti-BCR-ABL efficacy of T-helper or cytotoxic T lymphocytes (18,19), and the restoration of immune control associated with programmed cell death-1 (PD-1) inhibition in molecular (RM3.0) or deep-response CML patients (20). Thus, CML is a candidate for new immunotherapies.…”

Biology-Driven Approaches to Prevent and Treat Relapse of Myeloid Neoplasia after Allogeneic Hematopoietic Stem Cell Transplantation

“…Along with T cells, the natural killer (NK) cell compartment plays an important role for relapse prevention, because NK cells are activated owing to the absence of self-HLA class I molecules on malignant cells. Reduced expression of HLA class II molecules has been observed in, for example, chronic myelogenous leukemia [24], Hodgkin lymphoma, aggressive B cell lymphomas [25,26], and relapsed leukemia in patients without genomic HLA loss [27,28]. Reduced expression of HLA class II molecules has been shown to promote leukemia relapse, which could be counterbalanced by IFN-g treatment to enhance HLA expression [29].…”