Immunologically-mediated tumour cell apoptosis: the role of TRAIL in T cell and cytokine-mediated responses to melanoma.

Immune responses against human melanoma are common and are believed to influence the natural history of the disease. In particular, CD4 T cell infiltrates are associated with regression of primary melanoma and with responses to treatment with interferon-alpha2 (IFN-alpha2). Our studies have shown that CD4 T cells appear to kill melanoma by means of a member of the tumour necrosis factor (TNF) family expressed on their surface and called TNF related apoptosis inducing ligand (TRAIL). Moreover, sensitivity to TRAIL also predicts responsiveness of melanoma to CD4 T cells. TRAIL is not expressed on resting lymphocytes but is expressed at high levels after exposure to IFN-alpha2 and on activated T cells. Lymphocytes from melanoma patients in early stages of the disease show high levels of expression after exposure to IFN-alpha2 and IFN-gamma but expression was less on lymphocytes from stage IV patients. This may be due to factors from melanoma cells in that supernatants from some melanoma cultures suppressed IFN-alpha2 upregulation of TRAIL. Sensitivity of melanoma cells to TRAIL can be increased by inhibition of the activation of NF-kappaB and anti-apoptotic events downstream of NF-kappaB. These results suggest that TRAIL may be an important mediator of responses against melanoma induced by immunotherapy or by treatment with IFN-alpha2 and interleukin-2. Studies on surgical biopsies of melanoma however show that fresh isolates appear less sensitive to TRAIL-induced apoptosis and effective therapy may involve combinations with other agents.