Dysregulation of DNAM-1-Mediated NK Cell Anti-Cancer Responses in the Tumor Microenvironment

Abstract

NK cells play a pivotal role in anti-cancer immune responses, thanks to the expression of a wide array of inhibitory and activating receptors that regulate their cytotoxicity against transformed cells while preserving healthy cells from lysis. However, NK cells exhibit severe dysfunction in the tumor microenvironment, mainly due to the reduction of activating receptors and the induction or increased expression of inhibitory checkpoint receptors. An activating receptor that plays a central role in tumor recognition is the DNAM-1 receptor. It recognizes PVR and Nectin2 adhesion molecules, which are frequently overexpressed on the surface of cancerous cells. These ligands are also able to trigger inhibitory signals via immune checkpoint receptors that are upregulated in the tumor microenvironment and can counteract DNAM-1 activation. Among them, TIGIT has recently gained significant attention, since its targeting results in improved anti-tumor immune responses. This review aims to summarize how the recognition of PVR and Nectin2 by paired co-stimulatory/inhibitory receptors regulates NK cell-mediated clearance of transformed cells. Therapeutic approaches with the potential to reverse DNAM-1 dysfunction in the tumor microenvironment will be also discussed.

Keywords: DNAM-1 activating receptor; DNAM-1 dysfunction; NK cell immune surveillance; tumor microenvironment.

Figure 1

Schematic representation of different activating and inhibitory receptors sharing PVR and Nectin2 ligands. PVR and Nectin2 are frequently over-expressed on different types of tumors. They are both recognized with different binding affinities by DNAM-1, CD96, TIGIT and CD112R expressed on NK cells. The arrows indicate the functional interaction between the receptors and their common ligands promoting positive (+) or negative (−) signals, and the thickness of the arrows is proportional to the relative binding affinity. The strongest interactions are between TIGIT and PVR, and CD112R and Nectin2.

Figure 2

Different mechanisms of DNAM-1 dysfunction in the tumor microenvironment. (A) Chronic engagement of DNAM-1 with its ligands promotes receptor internalization and impairs DNAM-1-mediated functions. (B) Post-translational modifications are responsible for PVR and Nectin2 intracellular retention and/or degradation, thus preventing tumor cell recognition by NK cells. Soluble PVR isoforms can bind DNAM-1, interfering with recognition of membrane-bound ligands. (C) In advanced tumor stages, the up-regulation of checkpoint receptors competing with DNAM-1 for ligand binding hampers DNAM-1 anti-tumor functions. (D) PD-1 engagement is followed by dephosphorylation of DNAM-1 intracellular domains preventing signal transduction. NKG2D chronic engagement by tumor cells directly interferes with DNAM-1-triggered signaling and indirectly inhibits DNAM-1 activation by the up-regulation of TIGIT expression.