Programmed Cell Death-Ligand 2: A Neglected But Important Target in the Immune Response to Cancer?

Programmed cell death-ligand 2 (PD-L2) is one of the two ligands of the programmed cell death-1 (PD-1) receptor, an inhibitory protein mainly expressed on activated immune cells that is targeted in the clinic, with successful and remarkable results. The PD-1/PD-Ls axis was shown to be one of the most relevant immunosuppressive pathways in the immune microenvironment, and blocking this interaction gave rise to an impressive clinical benefit in a broad variety of solid and hematological malignancies. Although PD-L2 has been historically considered a minor ligand, it binds to PD-1 with a two- to six-fold higher affinity as compared to PD-L1. PD-L2 can be expressed by immune, stromal, or tumor cells. The aims of this narrative review are to summarize PD-L2 biology in the physiological responses of the immune system and its role, expression, and clinical significance in cancer.