Regulation of NKG2D signaling during the epithelial-to-mesenchymal transition

Abstract

The plasma membrane receptor natural killer group 2 member D (NKG2D) underpins a major mechanism whereby natural killer (NK) and T cells recognize malignant cells. We have recently demonstrated that the epithelial-to-mesenchymal transition, one of the first steps of metastatic dissemination, is under the control of an immunological checkpoint that relies on NKG2D-mediated immune responses.

Keywords: MICA/B; NK cells; NKG2D; ULBP; colorectal carcinoma; epithelial-to-mesenchymal transition.

Figure 1. NKG2D-mediated immune response during the epithelial-to-mesenchymal transition. MHC class I polypeptide-related sequence (MIC)A/B are expressed on the apical surface of healthy colonocytes, and there is no evidence of a physical interaction between these molecules and natural killer group 2 member D (NKG2D), which is expressed by lymphocytes infiltrating the basal side of the epithelium and the lamina propria. This prevents the recognition of healthy cells by natural killer (NK) cells and hence the development of autoimmune responses. The expression of NKG2D ligands (NKG2DLs) is increased on the surface of malignant cells. Moreover, along with the loss of epithelial integrity and polarity that accompanies the so-called “epithelial-to-mesenchymal transition” (EMT), MICA/B can diffuse all over the plasma membrane of mesenchymal cells, leading to their elimination by NK cells. Only malignant cells that evolve mechanisms to circumvent NKG2D-mediated immune responses, such as the repression of NKG2DLs, are able to establish advanced lesions and metastases.