Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance

Abstract

Upregulation of the inducible gene products MICA (human) and Rae-1 (mouse) may promote tumor surveillance and autoimmunity by engaging the activating receptor NKG2D on natural killer (NK) cells and T cells. Nevertheless, sustained expression of MICA by tumors can also elicit NKG2D downregulation, perhaps indicating 'immunoevasion'. Investigating this paradox, we report here that constitutive Rae-1epsilon transgene expression in normal epithelium elicited local and systemic NKG2D downregulation, generalized but reversible defects in NK cell-mediated cytotoxicity and mild CD8(+) T cell defects. The extent of NKG2D downregulation correlated well with the incidence and progression of cutaneous carcinogenesis, emphasizing the utility of NKG2D as a marker of tumor resistance. Thus, NKG2D engagement is a natural mediator of immunosurveillance, which can be compromised by locally sustained ligand expression but potentially restored by innate immune activation.

Natural killer cell immune escape in acute myeloid leukemia

“…100 Importantly, this strategy must be examined with scrutiny because sustained exposure of NKG2D ligands, either membrane-bound or in soluble form, to their receptor results in reduced NKG2D expression and impaired NK cell killing capacity. [102][103][104] Finally, several cytokines (for example, IFN-a, IL-15, TGF-b) were demonstrated to affect NKG2D ligand expression, but have not been tested on AML cells. 4,84 The proteasome inhibitor bortezomib and the histone deacetylase inhibitor depsipeptide were also shown to improve NK-cellmediated killing of AML cells through the death-receptor pathway TNF-related apoptosis-inducing ligand (TRAIL).…”

Primary Human Tumor Cells Expressing CD155 Impair Tumor Targeting by Down-Regulating DNAM-1 on NK Cells

“…Mechanisms such as shedding of ligands, chronic ligand exposure, and trogocytosis have been described (30,31,39,40). Interestingly, CD96, a NK cell receptor that like DNAM-1 binds CD155, was shown to be down-regulated upon ligand engagement (41).…”

Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo

“…20,21 Thus, it is possible that sustained engagement of NKG2D by iMICA protein might decrease the expression of NKG2D on the surface of NK cells. However, we found that the expression of NKG2D in NK cells activated for 1 week did not decrease when compared with freshly isolated NK cells (Figure 1e).…”