Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia

Abstract

NKG2D ligands (NKG2DLs) mark malignant cells for recognition by natural killer (NK) cells and cytotoxic T lymphocytes via the activating immunoreceptor NKG2D. This led to the hypothesis that NKG2DLs play a critical role in tumor immune surveillance. The human NKG2DLs MICA and MICB are expressed on tumors of epithelial origin in vivo. For the other recently described set of human NKG2DLs, the UL16-binding proteins (ULBPs), expression in vivo is as yet undefined. In this study we investigated expression and function of NKG2DLs in leukemia using a panel of newly generated NKG2DL-specific monoclonal antibodies. We report that leukemia cells from patients variously express MIC and ULBP molecules on the cell surface with MICA most frequently detected. Patient leukemia cells expressing MICA were lysed by NK cells in an NKG2D-dependent fashion. Sera of patients, but not of healthy donors, contained elevated levels of soluble MICA (sMICA). We also detected increased sMICB levels in patient sera using a newly established MICB-specific enzyme-linked immunosorbent assay. Reduction of leukemia MIC surface expression by shedding may impair NKG2D-mediated immune surveillance of leukemias. In addition, determination of sMICA and sMICB levels may be implemented as a prognostic parameter in patients with hematopoietic malignancies.

Wiskott‐Aldrich syndrome protein (WASp) and N‐WASp are involved in the regulation of NK‐cell migration upon NKG2D activation

“…Recent works have shown the remarkable role of ULBP2 as a marker for disease progression [8,21]. In addition, it has been reported that proteasome inhibitor treatment leads to a higher sensitivity to NK-cell-mediated killing by upregulation of ULBP2 expression [22], supporting its potential relevance in the development of anticancer therapy.…”

“…This effect was abrogated by costimulation of the NKG2A receptor, while the activation of this receptor alone did not affect cell migration. These results are in keeping with the study of Culley et al [20], which describes that activating signals in NK cells, such as interaction of NKG2D with MICA promotes a stop signal to form the IS, while inhibitory signals may reverse this effect.Recent works have shown the remarkable role of ULBP2 as a marker for disease progression [8,21]. In addition, it has been reported that proteasome inhibitor treatment leads to a higher sensitivity to NK-cell-mediated killing by upregulation of ULBP2 expression [22], supporting its potential relevance in the development of anticancer therapy.…”

“…High expression of MICA and ULBP2 is detected in ovarian cancer tissue and related to a poor prognosis [7]. Expression of NKG2DL on the cell surface of leukemia cells has also been described [8]. Furthermore, it has been described that the soluble forms of NKG2DL may be released from tumor cells [9,10] and that elevated levels are found in multiple pathologies, such as epithelial tumors or hematopoietic malignancies [11].…”

Natural killer cell immune escape in acute myeloid leukemia

“…For more than a decade, however, an impaired NK cell cytotoxic capacity in AML patients is acknowledged. [17][18][19][20][21][22] NK-cellmediated killing of a target cell depends on the balance between Impaired NK cell-mediated cytotoxicity AML cell shedding of NKG2D-L MIC and ULBP molecules 43,44 Reduced receptor expression and impaired NK cell-mediated cytotoxicity AML cell GITRL expression 45 Surface and soluble GITRL expression (surface expression is related to monocytic differentiation)…”

“…40,41 AML cells themselves contribute to impaired NK cell-mediated killing by decreased or absent expression of surface ligands for various NK cell activating receptors, including NCRs and NKG2D. 27,28,42,43 Furthermore, AML cells can shed ligands for NKG2D, as demonstrated by the increased serum levels of MHC class I chain-related genes A and B (MICA/B) in AML patients compared with healthy controls. 43,44 These soluble ligands may provide a chronic systemic stimulus to NK cells resulting in reduced receptor expression and impaired NK cell-mediated cytotoxicity (Table 1).…”