The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective induction of cell death in potentially dangerous and superfluous cells to providing costimulatory signals that help mount an effective immune response. This diverse and important regulatory role in immunity has sparked great interest in the development of TNFL/TNFR-targeted cancer immunotherapeutics. In this review, I will discuss the biology of the most prominent proapoptotic and co-stimulatory TNF ligands and review their current status in cancer immunotherapy. 1. Introduction The tumor necrosis factor (TNF) superfamily is comprised of 27 ligands that all share the hallmark extracellular TNF homology domain (THD) [1]. This THD triggers formation of non-covalent homotrimers. TNF ligands are typically expressed as type II transmembrane proteins,but in most ligands the extracellular domain can be subject to proteolytic processing into a soluble ligand. TNF ligands exert their biological function by binding to and activation of members of the TNF receptor (TNFR) superfamily. These TNFRs are typically expressed as trimeric type I transmembrane proteins and contain one to six cysteine-rich domains (CRDs) in their extracellular domain [2]. The TNF ligand superfamily has diverse functions in the immune system, one of which is the induction of apoptotic cell death in target cells. This function is performed by a family subgroup coined the Death Inducing Ligands, comprising the archetypal member TNF, FasL, and TRAIL. These Death Inducing Ligands bind to and activate cognate members of a TNFR subgroup termed the Death Receptors (DRs). DRs are characterized by the hallmark intracellular Death Domain (DD) that transmits the apoptotic signal. In general, ligand/receptor interaction induces formation of a Death Inducing Signaling Complex (DISC) to the cytoplasmic DD [3]. This DISC comprises the adaptor protein Fas-associated death domain (FADD) and an inactive proform of the cysteine protease procaspase-8. In addition to procaspase-8, the inhibitory caspase-8 homologue cFLIP can be recruited to this complex [4]. Within the DISC, caspase-8 is auto-proteolytically processed via proximity-induced activation [5], whereupon a catalytic caspase-mediated pathway of apoptosis ensures execution of apoptotic cell death. All of these three proapoptotic TNF ligands hold considerable
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