PD-L1 Domain Organization, Signaling Motifs and Interactors in Cancer Immunotherapy

Programmed cell death 1 ligand-1 (PD-L1)/ programmed cell death-1 (PD-1) blockade immunotherapies have revolutionized oncology. These therapies consist of blocking the binding of PD-1 expressed in T cells to its ligand PD-L1 expressed by cancer cells using monoclonal antibodies administered systemically. When localized on the surface of cancer cells, PD-L1 delivers inhibitory signals to the T cell through PD-1, inactivating T cell effector functions. In addition to this mechanism of action, PD-L1 also delivers intracellular signals to the cancer cell, in a process termed “reverse signaling” or “intrinsic signaling”. This intrinsic signal transduction takes place both in the presence and in the absence of PD-1 binding, and contributes to the survival of cancer cells in response to pro-apoptotic stimuli. PD-L1 intrinsic signaling functions are much wider than originally suspected, and include protection from apoptosis, enhancement of cancer cell proliferation, regulating DNA damage responses and even acting as a co-transcriptional transactivator. The mechanisms governing these functions are currently under intensive research. In this review we provide a perspective on PD-L1 research from distinct points of view, but especially focusing on its structure, signaling motifs and interactors.