TRAIL (TNF-Related Apoptosis-Inducing Ligand) and the TRAIL receptors were originally isolated based to their homology to tumor necrosis factor (TNF) and TNF receptor (TNFR) family members. 1–3 In humans, five TRAIL receptors have been characterized. Two of these receptors, DR4 and DR5, contain an intracellular protein motif known as a death domain, which can transmit an apoptotic signal. Two additional receptors, DcR1 and DcR2, lack a functional death domain and appear to function as decoy receptors to inhibit signaling by TRAIL. 4 The fifth receptor, osteoprotegerin (OPG), has been shown to bind TRAIL in vitro but has low affinity for the ligand at physiological temperatures; 5 therefore, it is unclear as to whether it is a true receptor for TRAIL. In mice, one full length signaling receptor (TRAIL-R) and two decoy receptors lacking death domains have been identified. 6, 7 Like Fas and TNFR, TRAIL-R induces apoptosis in a broad range of transformed cell lines in a FADD-and caspase-8-dependent manner. 8–11 In contrast to Fas and TNFR, most nontransformed cells are resistant to TRAIL-R-mediated death; 1, 12, 13 as a result, there is considerable interest in the potential role of TRAIL as a cancer therapeutic. Several studies have examined the in vivo role of TRAIL/TRAIL-R signaling in tumor immunity. TRAIL expression has been observed on the surface of activated CD8þ T cells, NK, and NKT cells, which correlated with their ability to kill tumor cells via a TRAIL-dependent mechanism. 14–16 TRAIL blocking antibodies can also inhibit NK cell cytotoxicity against mouse fibrosarcoma L929 target cells. 17 In vivo TRAIL administration led to regression of exogenously introduced TRAIL-sensitive tumors in mice. 13 In addition, blocking antibodies to TRAIL can increase tumor growth and metastasis in methylcholanthrene (MCA)-treated mice as well as mice inoculated with TRAIL-sensitive tumors. 18, 19 Finally, TRAIL-deficient mice are more sensitive to MCA-induced tumorigenesis, less able to reject implanted TRAIL-sensitive tumors, and less responsive to the immunotherapeutic agent alpha-galactosylceramide (a-GalCer). 20, 21 These data indicate that TRAIL can induce rejection or apoptosis of tumor cells in vivo, but its role in immune surveillance of spontaneously developing tumors has not been fully investigated. We previously described the generation of TRAIL-R-deficient mice, which do not spontaneously develop tumors (Diehl G, et al. submitted). To determine what role, if any, the TRAIL/TRAIL-R pathway plays in the control of spontaneously developing tumors, we crossed the TRAIL-R null allele into the p53-deficient and Min (for Mouse Intestinal Neoplasia) tumor models.

The p53 tumor suppressor gene is mutated in a large percentage of human malignancies, including tumors of the colon, breast, lung, and brain. 22 Individuals who inherit a mutant allele of p53 are susceptible to a wide range of tumor types. Mice deficient for p53 are viable and develop normally, but 50% develop tumors by 20 weeks of age and all develop tumors by 6 months of age. 22–24 The vast majority of tumors in p53-deficient animals are lymphomas, making these animals a good lymphoma model. Most of the lymphomas are of thymic origin and are composed primarily of immature CD4/CD8 double-positive cells. 25 p53þ/À mice also develop tumors, although at a much later age, and these tumors are primarily sarcomas. In most cases, tumorigenesis in these animals is accompanied by loss of the wild-type p53 allele. 22 A previous study has suggested a role for TRAIL in the control of p53 tumorigenesis. 19 However, in these experiments, TRAIL neutralizing …