NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment

Abstract

The antitumor functions of NK cells are regulated by the integration of positive and negative signals triggered by numerous membrane receptors present on the NK cells themselves. Among the main activating receptors, NKG2D binds several stress-induced molecules on tumor targets. Engagement of NKG2D by its ligands (NKG2D-Ls) induces NK cell activation leading to production of cytokines and target cell lysis. These effects have therapeutic potential as NKG2D-Ls are widely expressed by solid tumors, whereas their expression in healthy cells is limited. Here, we describe the genetic and environmental factors regulating the NKG2D/NKG2D-L pathway in tumors. NKG2D-L expression is linked to cellular stress and cell proliferation, and has been associated with oncogenic mutations. Tumors have been found to alter their to NKG2D-L expression as they progress, which interferes with the antitumor function of the pathway. Nevertheless, this pathway could be advantageously exploited for cancer therapy. Various cancer treatments, including chemotherapy and targeted therapies, indirectly interfere with the cellular and soluble forms of NKG2D-Ls. In addition, NKG2D introduced into chimeric antigen receptors in T- and NK cells is a promising tumor immunotherapy approach.

Epithelial‐mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1

“…Therefore, the survival of CTCs might be a vulnerable aspect of malignant tumor metastasis, and thus the mechanism enabling CTCs to evade immune effector cell killing may be an important target for prospective cancer therapy research. Studies have shown that tumor cells may shed or otherwise restrict the presentation of NK‐cell receptor D (NKG2D) ligands, such as MICA, MICB, and ULBPs, involved in their recognition by NK cells or cytotoxic T lymphocytes (CTLs), or downregulate the expression of other factors that promote the activation of tumor‐specific immune responses . Furthermore, it is established that tumor cells that undergo EMT acquire phenotypic changes, involving the upregulation and downregulation of molecules.…”

Metformin inhibits cervical cancer cell proliferation by modulating PI3K/Akt-induced major histocompatibility complex class I-related chain A gene expression

“…It is a stress marker and is expressed in pathogenic bacteria, tumors, and organ transplant recipients [30]. MICA is the receptor of NKG2D, an important activating protein on the NK cell surface, and NK cells play a very important role in tumor innate immunity to kill tumor cells by recognizing tumor cell surface markers and producing a cytotoxic effect [51]. Previous studies have shown that high glucose protects pancreatic cancer from NK cell-mediated killing through suppressing MICA/B expression.…”

Epigenetic therapy remodels the immune synaptic cytoskeleton to potentiate cancer susceptibility to γδ T cells

“…1E) (15,16). These molecules have been identified as targets for tumor immunosurveillance by the innate immune system and may elicit antitumor immunity without the requirement for conventional MHC-restricted antigen presentation (17). In addition, the two death receptors (i.e., TRAIL-R1 and TRAIL-R2) for TNFrelated apoptosis-inducing ligand (TRAIL) that induce cancer apoptosis as part of immune surveillance (18) were significantly upregulated in D3R3 (Fig.…”