Role of NKG2D and its ligands in cancer immunotherapy

Abstract

The activating receptor natural killer group 2, member D (NKG2D) is involved in both innate and adaptive immunities, and functions as a "master switch" in determining the activation status of natural killer (NK) cells. NKG2D binds to a diverse family of ligand molecules, which are only expressed at low levels in normal cells but can be upregulated by a cellular stress response. The NKG2D-NKG2D ligand (NKG2DL) pathway has been considered to be promising target for immunotherapy because of the selective expression of "stress-induced ligands" on tumor cells and the strong NK cell activating potency of NKG2D. Diverse strategies that are aimed at targeting the NKG2D pathway for cancer therapy are based on a thorough understanding of this mechanism, as well as that of NKG2D-mediated cancer immunity. In this review, we summarize the major findings regarding the antitumor immune response mediated by the NKG2D receptor and its ligands, and discuss the potential clinical applications of targeting the NKG2D/NKG2DL pathway for immunotherapy in cancer patients.

Keywords: Cancer immunotherapy; NKG2D; NKG2D ligands; immunity.

Conflict of interest statement

None.

AJCR Copyright © 2019.

Figures

Figure 1

Activation of NK cells by the NKG2D/NKG2DL pathway. A. The balance of signals mediated by activation and inhibition of specific receptors determines the activation of NK cells. B. Tumor cells overexpress NKG2DLs that can be recognized by the NKG2D receptor, which function as a “master switch” and elicits NKG2D-mediated cytotoxicity. This figure was created using Adobe Illustrator.

Figure 2

NKG2D/NKG2DL interaction activates NK cells. The activating receptor NKG2D can directly bind to a diverse family of ligand molecules expressed on the surface of tumor cells. In NK cells, NKG2D interacts with either DAP10 (both human and mouse) or DAP12 (mouse only) and induces cytotoxicity and IFN-γ production. DAP10/YXXM-mediated signaling regulates NK cell cytotoxicity via the Grb2 and PI3K pathway, while the NKG2D-DAP12 complex is involved in IFN-γ production through the Syk and ZAP70 pathway. NKG2D, Natural killer group 2, member D; NKG2DLs, NKG2D ligands. This figure was created using Adobe Illustrator.

Figure 3

The structure of NKG2DLs. Humans have two main types of ligands for NKG2D (left panel): a family of class-I chain-related proteins A and B (MICA and MICB) and a family of six cytomegaloviral UL16-binding proteins (ULBP 1-6). Mouse NKG2DLs are mainly RAET1 isoforms, H60 families, and MULT1 (right panel). The structure of NKG2DLs in humans and mice is similar. The ligands can be classified into three general structures. MICA and MICB are transmembrane proteins with three extracellular domains analogous to the α1-α3 domains of MHC Ia proteins. The remaining human NKG2DLs and all mouse NKG2DLs contain two domains analogous to α1 and α2 of MHC Ia proteins but lack the α3-like domain. The structures (Protein Data Bank codes) of MICA-human NKG2D (1HYR), ULBP3-human NKG2D (1KCG), and (RAE-1β)-mouse NKG2D (4PP8) are shown.

Figure 4

The dual functions of NKG2D/NKG2DL in tumor immunity. A. Induction of NKG2DLs on tumor cells induces immune surveillance via binding to NKG2D receptors expressed on NK and T cells. B. Failure to kill tumor cells due to the shedding of NKG2DLs by metalloproteinases. TGF-β allows immune surveillance escape by inhibiting T and NK cell function. NKG2D, Natural killer group 2, member D; sNKG2DLs, soluble NKG2D ligands. This figure was created using Adobe Illustrator.

Figure 5

Strategies for targeting the NKG2D/NKG2DL axis for cancer immunotherapy. A variety of cytokines, such as IL-2, -12, -15, and -18, can modulate the function of NK cells. Strategies, such as CH3SeH HDAC, microRNA, and targeting post-transcriptional mechanisms, also play an important role in NKG2D-mediated cytotoxicity by regulating the NKG2DL expression on the tumor cell. Chemotherapy, irradiation and ionizing radiation, and current cancer therapeutic modalities induce DNA damage and upregulate the expression of NKG2DLs in cancer via the ATM/ATR pathway. Small molecule inhibitors blocking MMP and ADAM were developed to decrease shedding of soluble NKG2DLs. NKG2DL, NKG2D ligands; MMP, matrix metalloprotease; ADAM, a disintegrin and metalloprotease; HDAC, histone deacetylase. This figure was created using Adobe Illustrator.