Immunobiology and conflicting roles of the human NKG2D lymphocyte receptor and its ligands in cancer

Abstract

Cancers adopt diverse strategies to safeguard their survival, which often involve blinding or incapacitating the immune response, thereby gaining battleground advantage against the host. In immune responses against cancer, an important stimulatory lymphocyte receptor is NKG2D because the tumor-associated expression of its ligands promotes destruction of malignant cells. However, with advanced human cancers profound changes unfold wherein NKG2D and its ligands are targeted or exploited for immune evasion and suppression. This negative imprinting on the immune system may be accompanied by another functional state wherein cancer cells coopt expression of NKG2D to complement the presence of its ligands for self-stimulation of tumor growth and presumably malignant progression. This review emphasizes these conflicting functional dynamics at the immunity-cancer biology interface in humans, within an overview of the immunobiology of NKG2D and mechanisms underlying the regulation of its ligands in cancer, with reference to instructive clinical observations and translational approaches.

FIGURE 1

Schematic representation of NKG2D/ligand-mediated effects in cancer settings. (A) Tumor-associated NKG2D ligands trigger effector functions of NK cells and, via costimulation, of CD8 T cells. NKG2D-mediated CD8 T cell stimulation triggers FasL release. At this stage, the TCR, CD16, and the NKp30 and NKp46 NCRs are functionally expressed in complex with CD3ζ. (B) Persistence of tumor cell membrane-bound and soluble NKG2D ligands cause NKG2D downmodulation and functional impairment. Still functional NKG2D (see A and C) initiates FasL/Fas-mediated caspase activation and resultant CD3ζ loss. As a consequence, the functional capacities of the TCR, CD16, and NKp30 and NKp46, which all signal through CD3ζ, are impaired. (C) NKG2D costimulates proliferation, and IL-10, TGFβ and FasL release by immunosuppressive NKG2D⁺CD4⁺ T cells. (D) NKG2D⁺ cancer cells proliferate in response to autocrine NKG2D-mediated stimulation. See text for further explanations.