Beyond Cancer: Regulation and Function of PD-L1 in Health and Immune-Related Diseases

Abstract

Programmed Cell Death 1 Ligand 1 (PD-L1, CD274, B7-H1) is a transmembrane protein which is strongly involved in immune modulation, serving as checkpoint regulator. Interaction with its receptor, Programmed Cell Death Protein 1 (PD-1), induces an immune-suppressive signal, which modulates the activity of T cells and other effector cells. This mediates peripheral tolerance and contributes to tumor immune escape. PD-L1 became famous due to its deployment in cancer therapy, where blockage of PD-L1 with the help of therapeutic antagonistic antibodies achieved impressive clinical responses by reactivating effector cell functions against tumor cells. Therefore, in the past, the focus has been placed on PD-L1 expression and its function in various malignant cells, whereas its role in healthy tissue and diseases apart from cancer remained largely neglected. In this review, we summarize the function of PD-L1 in non-cancerous cells, outlining its discovery and origin, as well as its involvement in different cellular and immune-related processes. We provide an overview of transcriptional and translational regulation, and expression patterns of PD-L1 in different cells and organs, and illuminate the involvement of PD-L1 in different autoimmune diseases as well as in the context of transplantation and pregnancy.

The role of PD-1 signaling in health and immune-related diseases

“…Studies regarding the PD-1 pathway in the context of viral, bacterial, and parasitic infections are accumulating ( 46 , 59 , 75 – 78 ). During infection, peptide antigens from microbes are presented on MHC complexes to naive T cells by APCs.…”

“…Immune checkpoints are crucial regulators of the immune system for self-tolerance and the prevention of rejection in the context of transplantation. To date, PD-1 and its ligands have been reported to play a significant role in the balance between reactive T cells targeting the organ and tolerogenic Tregs ( 59 , 91 – 93 ). Upregulation of PD-1, PD-L1, and PD-L2 in a murine model of cardiac transplantation during the process of allogeneic rejection was observed compared with that in syngeneic transplants and normal tissues ( 94 ).…”

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

“…The immunosuppressive costimulatory signal receptor PD-1 is expressed on activated T and B cells [ 302 , 303 ]. PD-L1 is strongly expressed by various solid tumors, B tumor cells (including DLBCL and MM cells), and BM stromal cells [ 303 , 304 ].…”

“…Several mAbs against PD1 (nivolumab, pembrolizumab, and cemiplimab) or PD-L1 (e.g., atezolizumab and durvalumab) have been approved for the treatment of various solid tumors [ 305 , 306 ]. Anti-PD-1 mAbs promote tumor cell apoptosis by binding to T-cell PD-1 receptors and disrupting the interaction with PD-L1 molecules on tumor cells [ 302 ]. However, no significant objective responses were observed in two phase I/Ib trials of nivolumab as a monotherapy or a combination therapy in patients with R/R MM [ 307 , 308 ].…”

Dynamic Evaluation of Natural Killer Cells Subpopulations in COVID-19 Patients

“…Cancer research revealed that the antitumoral activity of NK cells is related to the differential expression of PD-1 molecules [ 18 ]. The interaction between PD-1 with its ligand PD-Ll exerts many effects by inhibiting the Ly T cytokines productions and the T cells proliferation, overall engaging a down-regulated signal for immune cell activities [ 19 ]. For NK cells, a higher PD-1 expression implies a reduced IFN gamma secretion, a lower degranulation degree, and reduced antitumoral properties [ 18 ].…”