PD-L1 and B7-1 Cis-Interaction: New Mechanisms in Immune Checkpoints and Immunotherapies

Dysregulation of immune checkpoints contributes to the pathogenesis of cancer, autoimmunity, and organ transplant rejection by mediating undesired immune responses. The limited long-term therapeutic efficacy of immunotherapies targeting immune checkpoints underscores the need to better understand the underlying biology of these proteins. Immune checkpoint receptor–ligand interactions most commonly occur in trans (e.g., the receptor and ligand are expressed on two different cells). The newly characterized PD-L1:B7-1 interaction occurs in cis (e.g., the receptor and ligand are expressed on the same cell). The PD-L1:B7-1 cis-interaction alters the interactions between CD28, CTLA-4, B7-1, PD-L1, and PD-1, and may underlie the efficacy of immunotherapies in a variety of treatment settings. Immune checkpoints negatively regulate immune cell responses. Programmed cell death protein 1:programmed death ligand 1 (PD-1:PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4):B7-1 are among the most important immune checkpoint pathways, and are key targets for immunotherapies that seek to modulate the balance between stimulatory and inhibitory signals to lead to favorable therapeutic outcomes. The current dogma of these two immune checkpoint pathways has regarded them as independent with no interactions. However, the newly characterized PD-L1:B7-1 ligand–ligand cis-interaction and its ability to bind CTLA-4 and CD28, but not PD-1, suggests that these pathways have significant crosstalk. Here, we propose that the PD-L1:B7-1 cis-interaction brings novel mechanistic understanding of these pathways, new insights into mechanisms of current immunotherapies, and fresh ideas to develop better treatments in a variety of therapeutic settings. Immune checkpoints negatively regulate immune cell responses. Programmed cell death protein 1:programmed death ligand 1 (PD-1:PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4):B7-1 are among the most important immune checkpoint pathways, and are key targets for immunotherapies that seek to modulate the balance between stimulatory and inhibitory signals to lead to favorable therapeutic outcomes. The current dogma of these two immune checkpoint pathways has regarded them as independent with no interactions. However, the newly characterized PD-L1:B7-1 ligand–ligand cis-interaction and its ability to bind CTLA-4 and CD28, but not PD-1, suggests that these pathways have significant crosstalk. Here, we propose that the PD-L1:B7-1 cis-interaction brings novel mechanistic understanding of these pathways, new insights into mechanisms of current immunotherapies, and fresh ideas to develop better treatments in a variety of therapeutic settings. immune cells that help T cells recognize target antigens by processing and presenting these proteins on their cell surface. diseases in which the immune system attacks self-antigens. an immune checkpoint ligand that can induce a stimulatory or inhibitory immune response. an immune receptor that transmits co-stimulatory signals on T cells and natural killer cells. a process usually described in T cells in which cells gain the ability to exert their mechanistic functions through specific protein interactions. a protein–protein interaction that occurs on the same cell. an inhibitory immune checkpoint receptor that inhibits co-stimulation. a phenotypic state describing abnormal cellular responses. a highly regulated process in which extracellular material is brought into the cell. proteins that regulate immune cell responses through inhibition. a therapeutic strategy in which inhibitory proteins that restrain immune responses are blocked to improve immune responses. the process by which cells prevent recognition by the body’s immune system. an immune checkpoint receptor that transduces inhibitory signal. an immune checkpoint ligand that, upon binding to the PD-1 receptor, can induce inhibitory signals. proteins that dephosphorylate other proteins by removing bound phosphate groups. a protein complex on T cells that recognizes antigens presented by APCs. a protein–protein interaction that occurs on different cells. the process by which proteins from one cell membrane are transferred to another cell membrane.