Affiliation:
1. Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy
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.
Funder
Italian Association for Cancer Research
Istituto Pasteur Italia—Fondazione Cenci Bolognetti
Reference133 articles.
1. Human natural killer cells;Caligiuri;Blood,2008
2. NK cells and cancer: You can teach innate cells new tricks;Morvan;Nat. Rev. Cancer,2016
3. Molgora, M., Cortez, V.S., and Colonna, M. (2021). Killing the Invaders: NK Cell Impact in Tumors and Anti-Tumor Therapy. Cancers, 13.
4. Natural killer cells and type 1 innate lymphoid cells in cancer;Lopes;Semin. Immunol.,2023
5. Regulation of Ligands for the NKG2D Activating Receptor;Raulet;Annu. Rev. Immunol.,2013