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

Simple Summary Immune system counteracts tumor growth through a coordinated action of several innate and adaptative cells able to detect and eliminate altered cells. Among immune cells able to kill tumor cells, Natural killer (NK) cells belong to the innate arm of the immune system and distinguish cancerous from healthy cells thank to the expression of a wide array of activating and inhibitory receptors. DNAM-1 is an activating receptor that binds PVR and Nectin2 adhesion molecules frequently overexpressed on the surface of cancerous cells, thus representing a central receptor in tumor recognition. However, PVR and Nectin2 are also recognized by inhibitory receptors that are upregulated in tumor microenvironment and can counteract DNAM-1 activation, leading to NK cells hypo-functionality. This review focuses on the main potential molecular mechanisms responsible for the impairment of DNAM-1 functionality during tumor progression. Moreover, therapeutic approaches able to reverse DNAM-1 dysfunction and NK cell hypo-responsiveness will be also summarized.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.