The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that selectively induces apoptosis in tumor cells without harming normal cells, making it an attractive agent for cancer therapy. TRAIL induces apoptosis by binding to and activating its death receptors DR4 and DR5. Several TRAIL-based treatments have been developed, including recombinant forms of TRAIL and its death receptor agonist antibodies, but the efficacy of TRAIL-based therapies in clinical trials is modest. In addition to inducing cancer cell apoptosis, TRAIL is expressed in immune cells and plays a critical role in tumor surveillance. Emerging evidence indicates that the TRAIL pathway may interact with immune checkpoint proteins, including programmed death-ligand 1 (PD-L1), to modulate PD-L1-based tumor immunotherapies. Therefore, understanding the interaction between TRAIL and the immune checkpoint PD-L1 will lead to the development of new strategies to improve TRAIL- and PD-L1-based therapies. This review discusses recent findings on TRAIL-based therapy, resistance, and its involvement in tumor immunosurveillance.

Keywords: PD-L1; TRAIL; apoptosis; immunosurveillance; resistance.

Figure 1

Schematic overview of the TRAIL apoptosis pathway. TRAIL induces apoptosis by binding to death receptors 4/5. This promotes the trimerization of the death receptor, which recruits FADD and pro-caspase 8/10 to form DISC. The latter activates caspase 8/10, which activates caspase 3 to induce apoptosis. Caspase 8/10 can also convert BID to tBID by cleavage, increasing apoptosis. To accomplish this, tBID translocates to the mitochondria, activating BAX/BAK. The formation of mitochondrial pores is then mediated by activated BAX/BAK, resulting in the release of cytochrome c. An apoptosome is formed when Apaf-1 and pro-caspase 9 bind together. Caspase 9 is activated, which then activates caspases 3, 6, and 7 to increase apoptosis.

Figure 2

Mechanisms of TRAIL resistance. TRAIL resistance mechanisms can occur at any point along the TRAIL signaling pathway. Overexpression of decoy receptors, such as DcR1, DcR2, and OPG, can inhibit TRAIL-induced activation of DR4 and DR5 at the cell surface. TRAIL-induced apoptosis can also be inhibited by the inhibitory protein c-FLIP. This is accomplished by c-FLIP binding to FADD or procaspases 8/10 and inhibiting DISC formation. Antiapoptotic proteins (e.g., BCL-2, BCL-XL) can inhibit the TRAIL signaling pathway. These proteins bind to pro-apoptotic proteins (e.g., BAX), preventing MOMP, SMAC/DIABLO, and cytochrome c release. Two more downstream TRAIL signaling inhibitors are XIAP and IAP. These proteins prevent caspase 9, as well as caspases 3, 6 and 7 activation, which in turn inhibits apoptosis.

Figure 3

TRAIL and DR5 agonist antibodies increase PD-L1 expression. TRAIL can induce PD-L1 expression by activating the ERK and STAT3 pathways or inhibiting miR-429. DR5 agonist antibodies can induce PD-L1 expression by activating ROCK1. Induction of PD-L1 then results in EMT, cell survival, immune evasion, and resistance to TRAIL.