Interactions of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) with the Immune System: Implications for Inflammation and Cancer

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily. TRAIL has historically been distinct from the Fas ligand and TNFα in terms of selective apoptosis induction in tumor cells and has a nearly non-existent systemic toxicity. Consequently, in the search for an ideal drug for tumor therapy, TRAIL rapidly drew interest, promising effective tumor control with minimal side effects. However, euphoria gave way to disillusionment as it turned out that carcinoma cells possess or can acquire resistance to TRAIL-induced apoptosis. Additionally, studies on models of inflammation and autoimmunity revealed that TRAIL can influence immune cells in many different ways. While TRAIL was initially found to be an important player in tumor defense by natural killer cells or cytotoxic T cells, additional effects of TRAIL on regulatory T cells and effector T cells, as well as on neutrophilic granulocytes and antigen-presenting cells, became focuses of interest. The tumor-promoting effects of these interactions become particularly important for consideration in cases where tumors are resistant to TRAIL-induced apoptosis. Consequently, murine models have shown that TRAIL can impair the tumor microenvironment toward a more immunosuppressive type, thereby promoting tumor growth. This review summarizes the current state of knowledge on TRAIL's interactions with the immune system in the context of cancer.

Combination of long-acting TRAIL and tumor cell-targeted photodynamic therapy as a novel strategy to overcome chemotherapeutic multidrug resistance and TRAIL resistance of colorectal cancer

“…Apoptosis is an important mechanism for hemeostasis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent apoptosis inducer displayed on the surface of NK cells and cytotoxic T cells, plays important roles in tumor defense 7 . Recombinant soluble TRAIL is attractive as an antitumor agent due to its selective apoptosis induction in tumor cells overexpressing TRAIL receptors (death receptor 4, DR4, and death receptor 5, DR5) without systemic toxicity.…”

The non‐peptidomimetic IAP antagonist ASTX660 sensitizes colorectal cancer cells for extrinsic apoptosis

“…Besides TNF, lymphocytemediated tumor cell apoptosis also involves cytotoxic TRAIL signaling [39]. High expression levels of IAP contribute to TNF and TRAIL resistance in cancer cells and consequently attenuate the impact of cancer immunotherapy [39][40][41]. Combining cancer immunotherapy with the IAP-antagonizing activity of SM to enhance TNF-and TRAIL-mediated cancer cell killing via cytotoxic lymphocytes is therefore a reasonable therapeutic approach.…”

Neutrophils: Many Ways to Die

“…However, this is not the only way to activate apoptosis in neutrophils. It is recognized that apoptosis pathways can be activated in neutrophils after phagocytosis and ROS production, or during inflammatory processes when molecules such as extracellular matrix proteins ( 49 ), lipopolysaccharide (LPS), complement fragments ( 44 ), and cytokines, among others, favor the activation of TNF receptors and FaS/CD95 through JNK and NF-kB ( 50 , 51 ).…”