NKG2D and its ligands in cancer

Abstract

NKG2D is an activating immune receptor expressed by NK and effector T cells. Induced expression of NKG2D ligand on tumor cell surface during oncogenic insults renders cancer cells susceptible to immune destruction. In advanced human cancers, tumor cells shed NKG2D ligand to produce an immune soluble form as a means of immune evasion. Soluble NKG2D ligands have been associated with poor clinical prognosis in cancer patients. Harnessing NKG2D pathway is considered a viable avenue in cancer immunotherapy over recent years. In this review, we will discuss the progress and perspectives.

Figure 1:. Opposite impact of membrane-bound and soluble NKG2D ligands on tumor immunity.

Membrane-bound NKG2D ligands (NKG2D-L) stimulate tumor immunity by activating NK cells, co-stimulating CD8 T cell, NKT cell, and subsets of γδ T cells. Soluble NKG2D ligands (sNKG2D-L) incapacitate tumor immunity through perturbing NK cell hemostasis and function, impairing effector function of CD8 T, NKT, and γδ T cells, and expanding MDSC and TAMS.

Figure 2:. Proposed mechanism of action of clearing sMIC to re-invigorate the anti-tumor responses.

Clearance of sMIC was shown to alleviate global immune suppression, restore NK cell anti-tumor immunity, promote DC maturation, and augment antigen-specific CD8 T cell function.