The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia

Abstract

Soluble or membrane-anchored ligands of NKG2D and their receptor have a critical role in the elimination of tumor cells and disease progression. Plasma samples of 98 patients with B-cell chronic lymphocytic leukemia (CLL) were analyzed with specific ELISA systems for soluble major histocompatibility complex class I-related chains (sMICA and sMICB) and UL-16-binding proteins (ULBP1, 2, and 3). The flow cytometric analysis of MICA on CLL cells and natural killer group 2 member D (NKG2D) receptors on NK cells was performed after thawing of frozen peripheral blood lymphocytes of CLL patients (N ¼ 51). Levels of sMICA, sMICB, and sULBP2 were significantly increased (Po0.001) compared with 48 controls, whereas sULBP1 3 were not detectable in patients and controls. Levels of sMICA4990 pg/ml (P ¼ 0.014), sMICB4200 pg/ml (P ¼ 0.0001), and sULBP24105 pg/ml (Po0.0001) were associated with poor treatment-free survival (TFS). Neither MICA nor NKG2D expression could be related to clinical parameters. In multivariate analysis Binet stage (P ¼ 0.002), sULBP2 (P ¼ 0.002) and ZAP-70 (P ¼ 0.002) were independent predictive factors for TFS. In patients with Binet stage A, sULBP2 levels4105 pg/ml were strongly associated (P ¼ 0.0025) with poor TFS. Our data show that soluble but not membrane-anchored NKG2D ligands or receptors are of prognostic significance in CLL. Moreover, sULBP2 seems to be useful to identify early-stage patients with risk of disease progression.

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

“…MICA was already discussed as a prognostic factor in CLL. 17 However, we did not measure any significant overall difference in the expression levels of MICA in healthy vs CLL samples, although MICA plasma levels were significantly higher in CLL patients with advanced Binet stage C compared with Binet stage A ( Figure 4D). Taken together, patients with CLL showed elevated levels of soluble ligands for NKp30 and NKG2D in comparison with healthy individuals.…”

“…This is in line with a recent study that described a prognostic relevance for soluble ULBP2 level for the therapy-free survival of CLL patients. 17 A role for NKG2D was also suggested for the elimination of CLL cells by Vdelta1 T lymphocytes that may attenuate the progression of the disease. 42 Interestingly, neither any of these studies nor an independent report 15 demonstrate diminished NKG2D surface expression on NK cells from CLL patients, although an association of MICA levels with the down-modulation of NKG2D surface expression on CD8 T cells was recently described for CLL.…”

“…The NKG2D expression on NK cells in CLL was not significantly altered in comparison with healthy donors, [15][16][17] although it was reported that CLL patients have high serum levels of soluble NKG2D ligands. Shedding of NKG2D ligands from the surface of tumor cells represents an evasion strategy to escape from NK cell-mediated recognition and killing in hematologic and solid tumors.…”

“…Moreover, BAG6 level increased with progressed disease stage ( Figure 4A). Because a role for soluble NKG2D ligands in CLL is discussed, 16,17 in our analysis we included ligands for the activating NK cell receptor NKG2D (MICB, ULBP2, and MICA). Interestingly, we found significantly higher levels of MICB and ULBP2 in patients and levels increased with advanced disease stage ( Figure 4B-C).…”

Mono- and dual-targeting triplebodies activate natural killer cells and have anti-tumor activityin vitroandin vivoagainst chronic lymphocytic leukemia

“…1,13 Soluble NKG2D ligands including sMICA, sMICB and sULBP2 are of prognostic relevance in CLL. 14 Despite these immune escape mechanisms, NK cells are the main effectors of rituximab-induced response in CLL. 15 However, loss of CD20 antigen on CLL cells following rituximab treatment leads to expansion of antigen-loss variants resistant to rituximab.…”