Although cytotoxic T lymphocytes (CTLs) usually form an effective barrier against cancer, tumours have developed a number of mechanisms to escape the cellular immune response. In the 25 September issue of Proceedings of the National Academy of Sciences, Medema et al. report a new mechanism by which tumours evade T-cell-mediated cytolysis.

T cells induce apoptosis in target cells through two mechanisms — death-receptor activation and perforin/granzyme B (GrB)-induced exocytosis. GrB is secreted by CTL and enters the target cell through receptor-mediated endocytosis. Once inside the cell, GrB is released from the endosome into the cytoplasm, where it cleaves substrates such as BID and caspases, leading to apoptosis.

The serine protease inhibitor (PI)-9 irreversibly inhibits GrB and prevents CTL-mediated killing. This serpin has been shown to be expressed in lymphoid tissues and T cells, protecting CTLs from destruction by their own GrB. Medema et al. found that a variety of human tumours, including melanoma, breast, cervical and colon carcinoma, also express PI9, whereas a number of mouse tumours express Spi6 , the mouse homologue. Using an in vitro cytotoxicity assay, they showed that Spi6-expressing mouse tumours are resistant to CTL-induced apoptosis, whereas Spi6-negative tumour cell lines are not.

The authors transfected the gene that encodes Spi6 into tumour cell lines that do not normally express the protein but are resistant to death-receptor-mediated apoptosis. These cells managed to evade CTL-mediated lysis, whereas nontransfected cells did not. But, does Spi6 confer a survival advantage in vivo? The authors co-injected fluorescently labelled Spi6-expressing tumour cells and nonexpressing tumour cells into mice, and observed that the transfected cells had a distinct survival advantage.

A number of mechanisms have been reported by which tumour cells escape the death-receptor-mediated apoptotic pathway. Medema et al. offer the first demonstration of a mechanism by which tumours escape the perforin/GrB pathway. Cancer cells develop a number of techniques to interfere with the apoptotic signalling cascade; these must be identified before CTL-mediated immunotherapy can be further developed.