Natural killer group 2D receptor and its ligands in cancer immune escape

Shixin Duan,Yongzhen Mo,Can Guo,Weihua Guo,Guiyuan Li,Xiaoling Li,Chuting Liang,Wei Xiong,Fang Xiong,Fuyan Wang,Yian Wang,Yong Li,Zuxing Xu,Yunbo He,Zhaoyang Zeng

doi:10.1186/s12943-019-0956-8

Abstract

The immune system plays important roles in tumor development. According to the immune-editing theory, immune escape is the key to tumor survival, and exploring the mechanisms of tumor immune escape can provide a new basis for the treatment of tumors. In this review, we describe the mechanisms of natural killer group 2D (NKG2D) receptor and NKG2D ligand (NKG2DL) in tumor immune responses.Natural killer (NK) cells are important cytotoxic cells in the immune system, and the activated NKG2D receptor on the NK cell surface can bind to NKG2DL expressed in tumor cells, enabling NK cells to activate and kill tumor cells. However, tumors can escape the immune clearance mediated by NKG2D receptor/NKG2DL through various mechanisms. The expression of NKG2D receptor on NK cells can be regulated by cells, molecules, and hypoxia in the tumor microenvironment. Tumor cells regulate the expression of NKG2DL at the level of transcription, translation, and post-translation and thereby escape recognition by NK cells. In particular, viruses and hormones have special mechanisms to affect the expression of NKG2D receptor and NKG2DL. Therefore, NKG2D\\NKG2DL may have applications as targets for more effective antitumor therapy.

Highlights

The immune surveillance function of the immune system has been a hot topic in cancer research in recent years
Estrogen can help lung cancer cells escape natural killer group 2D (NKG2D)-mediated immune surveillance, and MHC class I molecule related proteins (MICA/B) mRNA and secreted protein levels are upregulated by estradiol in lung adenocarcinoma cell lines via a mechanism mediated by enhanced expression of ADAM17 [82]
Various components in the tumor microenvironment (TME) can regulate the expression of NKG2D receptor and NKG2D ligand (NKG2DL) through different mechanisms

Summary

Background

The immune surveillance function of the immune system has been a hot topic in cancer research in recent years. Studies have shown that the expression of TGF-β and NKG2DL (MICA/B, ULBP1–3) on the exosome surface in the extrapleural fluid of malignant mesothelioma downregulates the expression of NKG2D on immune cells, which is an important factor causing tumor immune escape [68]. The hepatitis C virus protein NS3/4A is associated with immune invasion and leads to decreased NKG2D ligand expression through unexplored mechanisms [73] These mechanisms inhibit the cytotoxic effects of NK cells via the downregulation of NKG2DL expression to achieve immune escape. Estrogen can help lung cancer cells escape NKG2D-mediated immune surveillance, and MICA/B mRNA and secreted protein levels are upregulated by estradiol in lung adenocarcinoma cell lines via a mechanism mediated by enhanced expression of ADAM17 [82]. Expanded NK cells can be combined with immunotherapeutic strategies, such as CAR-T, CAR-NK, and anti-PD-1/PD-L1 targeting, as well as chemotherapy, radiotherapy and tumor virus treatment strategies to achieve tumor elimination [95]

Conclusion and perspectives

Availability of data and materials Not applicable