The Diverse Function of PD-1/PD-L Pathway Beyond Cancer

Abstract

The recent success of PD-1 and PD-L1 blockade in cancer therapy illustrates the important role of the PD-1/PD-L1 pathway in the regulation of antitumor immune responses. However, signaling regulated by the PD-1/PD-L pathway is also associated with substantial inflammatory effects that can resemble those in autoimmune responses, chronic infection, and sepsis, consistent with the role of this pathway in balancing protective immunity and immunopathology, as well as in homeostasis and tolerance. Targeting PD-1/PD-L1 to treat cancer has shown benefits in many patients, suggesting a promising opportunity to target this pathway in autoimmune and inflammatory disorders. Here, we systematically evaluate the diverse biological functions of the PD-1/PD-L pathway in immune-mediated diseases and the relevant mechanisms that control these immune reactions.

Keywords: PD-1; PD-L1; autoimmune; chronic infection; sepsis.

Figure 1

Structural basis of PD-1/PD-L1 checkpoint blockade by antibodies and small molecules. (A) Structure of the PD-1 and PD-L1 complex (modified from PDB ID 3BIK). (B) Overall structure of the hPD-L1 and avelumab-Fab complex, the hPD-L1 and atezolizumab-Fab complex, the hPD-L1 and durvalumab-Fab complex, the hPD-L1 and BMS-936559-Fab complex, and the hPD-L1 and KN035 nanobody complex (magenta ribbon model) (modified from PDB IDs 5GRJ, 5X8L, 5X8M, 5GG7, and 5JDS, respectively). The heavy chain (V_H) and the light chain (V_L) of the antibody-Fab fragments are represented by red and yellow ribbon models, respectively. (C) Overall structure of the hPD-1 and nivolumab-Fab complex and the hPD-1 and pembrolizumab-Fab complex (modified from PDB IDs 5GGR and 5GGS, respectively). (D) Crystal structure of BMS-202 (non-peptide small molecule inhibitor, blue stick model) on the surface of hPD-L1 (light yellow ribbon structure) (modified from PDB ID 5J89). (E) Structure of macrocyclic peptide inhibitor “22” in complex with hPD-L1 (light yellow ribbon model = hPD-L1; blue ball and stick model = peptide) (modified from PDB ID 5O45).

Figure 2

The therapeutic potential of the PD-1/PD-L1 pathway in organ-related diseases. The PD-1/PD-L1 pathway is implicated in multiple diseases. In different diseases, the PD-1/PD-L1 pathway shows diverse functions. The therapeutic potential of the PD-1/PD-L1 pathway when treated via blockade or activation in diverse organ-related diseases is shown. COPD, chronic obstructive pulmonary disease.