DNAX accessory molecule-1 ligand (CD155 and CD112) (DNAM-1 ligand)

Tumor-expressed DNAM-1 ligands, primarily CD155 (PVR) and CD112 (Nectin-2), are cell surface glycoproteins that play a critical role in the regulation of the immune response against cancer (Bottino et al., 2003). These ligands are members of the immunoglobulin superfamily and are frequently overexpressed on various malignant cells, including those in melanoma, lung, and gastrointestinal cancers (Gao et al., 2017). They interact with the activating receptor DNAM-1 (CD226) on Natural Killer (NK) cells and CD8+ T cells to trigger cytolytic activity and cytokine production. However, they also bind to inhibitory receptors such as TIGIT, CD96, and PVRIG, which often have higher affinity for the ligands than DNAM-1, leading to immune evasion by the tumor (Johnston et al., 2014; Whelan et al., 2019). Therapeutic strategies focus on blocking these inhibitory interactions to favor DNAM-1-mediated activation or directly targeting the ligands to eliminate tumor cells. The clinical development of antibodies targeting the TIGIT/DNAM-1 axis represents a significant effort to overcome resistance to current PD-1/PD-L1 therapies. These ligands also serve as biomarkers for patient selection in trials involving TIGIT or PVRIG inhibitors. Furthermore, CD155 has been identified as a receptor for certain oncolytic viruses, providing an alternative therapeutic avenue.

Other names

CD155PVRPoliovirus receptorNecl-5CD112Nectin-2PVRL2Nectin cell adhesion molecule 2

The primary mechanism of action for drugs targeting this system is the blockade of inhibitory receptors (such as TIGIT, PVRIG, and CD96) to prevent them from sequestering the ligands (CD155 and CD112), thereby allowing the ligands to bind and activate the DNAM-1 receptor on immune cells. This restores the activating signal for NK and T cell-mediated tumor cell killing. Other approaches include using the ligands as entry points for oncolytic viruses like OBP-301.