Impact of Nectins and Nectin-like molecules and their receptors in T and NK cell function in cancer and aging

The family of Nectin and Nectin-like molecules (Necls) and their immunoreceptors are essential in the immune response against cancer. While primarily involved in cell adhesion, motility, and proliferation, some Nectin members also serve as ligands for both stimulatory and inhibitory immune receptors, influencing immune responses. The Nectin/Necls and their receptors form a complex regulatory axis crucial for natural killer (NK) and T cell activity. The most relevant ligands in this axis are the Nectin CD112 and the Nectin-like molecule CD155. Both are ligands for the activating receptor DNAX accessory molecule-1 (DNAM-1) and the inhibitory receptor T cell immunoreceptor with Ig and ITIM domains (TIGIT). Additionally, CD155 is a ligand for T cell activation induced late expression (TACTILE), and CD112 for poliovirus receptor related immunoglobulin domain containing (PVRIG), both inhibitory receptors. These ligands bind with higher affinity to their inhibitory receptors than to the activating receptor DNAM-1. Recent advances in cancer immunotherapy have focused on identifying new targets to overcome tumor resistance. Antibody-mediated blockade of inhibitory receptors such as TIGIT, TACTILE, and PVRIG on NK and T cells has shown promising results in animal models and clinical trials, helping to break immune tolerance. Aging significantly increases cancer risk and contributes to the deterioration of the immune response, impairing cancer immune surveillance. Aging is also associated with an altered tumor microenvironment, reducing immune cell infiltration and promoting tumor progression. In elderly cancer patients, both immunosenescence and cancer-related immunosuppression contribute to a defective immune response against tumor cells. Thus, cancer immunotherapy strategies should be personalized to overcome the dysfunctional immune responses in elderly cancer patients. Understanding these interactions, including ligand-receptor binding mechanisms, is vital for developing effective immunotherapies. Since cancer predominantly affects older adults, further research is needed to explore how aging impacts Nectin-receptor interactions and to tailor immunotherapy strategies for elderly patients.