Death Receptors and Their Ligands in Inflammatory Disease and Cancer

Abstract

On binding to their cognate ligands, death receptors can initiate a cascade of events that can result in two distinct outcomes: gene expression and cell death. The study of three different death receptor-ligand systems, the tumor necrosis factor (TNF)-TNF receptor 1 (TNFR1), the CD95L-CD95, and the TNF-related apoptosis-inducing ligand (TRAIL)-TRAIL-R1/2 system, has drawn the attention of generations of scientists over the past 50 years. This scientific journey, as often happens in science, has been anything but a straight line to success and discoveries in this field were often made by serendipity, catching the scientists by surprise. However, as Louis Pasteur pointed out, luck prefers the prepared mind. It is therefore not surprising that the most impactful discovery of the field to date, the fact that TNF inhibition serves as an effective treatment for several inflammatory and autoimmune diseases, has been like this. Luckily, the scientists who made this discovery were prepared and, most importantly, determined to harness their discovery for therapeutic benefit. Today's research on these death receptor-ligand systems has led to the discovery of a causal link between cell death induced by a variety of these systems and inflammation. In this review, we explain why we predict that therapeutic exploitation of this discovery may profoundly impact the future treatment of inflammatory disease and cancer.

Figure 1.

Tumor necrosis factor (TNF) receptor 1 (TNFR1)/DR3 and CD95/TNF-related apoptosis-inducing ligand (TRAIL)-R1/2 signaling pathways. Binding of TNF and TL1A to TNR-R1 and DR3, respectively, and CD95L and TRAIL to CD95 and TRAIL-R1/2, respectively, induces formation of a membrane-bound complex referred to as complex I or death-inducing signaling complex (DISC) in the case of CD95 and TRAIL-R1/2. TNFR1- and DR3-mediated complex I triggers gene expression via NF-κB and MAPKs, whereas the DISC has the potential to induce cell death by apoptosis or necroptosis. These two primary complexes dissociate from the respective receptors and incorporate additional proteins to form a secondary cytosolic complex called complex II. In the case of TNFR1 and TL1A, this complex induces caspase-8-mediated apoptosis or RIPK3/MLKL-mediated necroptosis. CD95 and TRAIL-R1/2 complex II triggers gene activation via NF-κB and MAPKs.

Figure 2.

Aberrant cell death in chronic inflammation. (A) Cell death is important for the repair and regeneration programs of different types of tissues, such as the epithelium of the skin and the intestine. Dying cells release factors that trigger the activation of an inflammatory program, whose ultimate purpose is to restore tissue integrity. (B) Deregulated cell death determines the persistence of tissue repair programs, which in turn leads to chronic inflammation, epithelial cell hyperproliferation, and, ultimately, to an autoinflammatory or autoimmune disorder. (DC) Dendritic cell.

Figure 3.

Mechanisms of death receptor (DR)-mediated immunosuppression in cancer. (A) The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/TRAIL-R1/2 system contributes to immunosuppression via distinct mechanisms. The activation of TRAIL-R1/2 expressed by cancer cells induces the secretion of cytokines that polarize monocytes into myeloid-derived suppressor cells (MDSCs) and alternatively activated (M2) macrophages. These cell types in turn create an immunosuppressive tumor microenvironment that prevents CD8⁺ T-cell-mediated antitumor immune responses. In addition, TRAIL expressed by cancer cells or noncancer cells in the tumor microenvironment can directly kill TRAIL-R1/2-expressing immune cells, which are required for mounting an adaptive immune response, such as dendritic cells (DCs) or T cells, and thereby interfere with adaptive antitumor immunity. (B) Cancer cells have the potential to induce the expression of CD95L on different cell types of the tumor microenvironment, such as endothelial cells, MDSCs, and fibroblasts. By cross-linking CD95 on the surface of T cells, CD95L induces their demise by apoptosis, thereby facilitating tumor cell evasion from an adaptive immune attack.