An unconventional TRAIL to cancer therapy.

Cellular immunotherapy offers novel, safe, and effective routes to treating cancer. However, approaches utilizing cytotoxic CD8(+) T cells are hampered by the need to identify suitable target antigens that are expressed by tumor cells but not healthy tissues, and that are recognized with sufficient affinity. Most importantly, the applicability of CD8(+) T-cell-based therapies is governed by the MHC restriction of tumor-specific epitopes, thereby limiting the potential benefit to patients carrying the appropriate MHC haplotype. Alternative approaches to harness the immune system against tumors exploit non-MHC-restricted γδ T cells that recognize stress-induced changes in transformed cells. A new report in this issue of the European Journal of Immunology [Eur. J. Immunol. 2013. 43: 3175-3182] shows that human γδ T cells efficiently kill lung cancer cells through recognition of the NKG2D ligand ULBP2 and secretion of soluble TRAIL. This finding provides new evidence for a TCR-independent cytotoxicity of γδ T cells and supports their promising potential for non-MHC-restricted immunotherapies.