Cytotoxic T lymphocytes (CTLs) mediate the host immune response against immunogenic tumours but, unfortunately, several hurdles limit their effective use as a cancer immunotherapy. For example, to be fully activated T cells require — besides T-cell receptor (TCR) activation — the co-stimulation of receptors such as CD28, but many tumours lack expression of ligands for CD28. Two groups now independently report that removing the E3 ubiquitin ligase Cblb (Casitas B-lineage lymphoma b), which makes T-cell activation independent of CD28 co-stimulation, protects mice against different types of transplanted and spontaneous tumours.

Jeffrey Chiang and colleagues studied in detail the effect of Cblb deletion on CD8+ T cells, which mediate the anti-tumour immune response. Following TCR stimulation, Cblb−/− CD8+ T cells showed increased proliferation and cytokine secretion compared with wild-type cells, without requiring CD28 co-stimulation. Proliferation and cytokine secretion were not reduced by transforming growth factor-β (TGFβ), which is often secreted by tumour cells and suppresses the CTL anti-tumour response. Interestingly, Stefanie Loeser and colleagues showed that Cblb−/− CD8+ T cells are also partially resistant to suppression mediated by regulatory T cells, another mechanism that can prevent CTL tumour killing.

To test the effect of Cblb deletion on the anti-tumour response in vivo, Chiang and colleagues subcutaneously injected Cblb−/− mice with weakly immunogenic and highly immunogenic cells from a mouse thymoma that does not express co-stimulatory molecules. Cblb deletion prevented or attenuated tumour growth compared with wild-type mice, regardless of the intrinsic immunogenicity of the tumour. Tumour rejection seemed to be independent of CD28 because tumour growth was also suppressed in Cblb−/−;Cd28−/− mice.

Similarly, Loeser and colleagues showed that Cblb−/− mice reject tumours derived from highly tumorigenic TC1 fibroblasts that express the E6 and E7 human papilloma virus 16 oncoproteins. Both groups confirmed that tumour rejection in Cblb−/− mice was mediated by CD8+ T cells, and that adoptively transferred CD8+ T cells from these animals induced the rejection of established tumours in recipient mice, although it has not yet been shown whether their cytotoxic activity is required.

So, does Cblb loss also reduce the development of spontaneous tumours? Chiang and colleagues crossed Cblb−/− mice with ataxia telangiectasia mutated ( Atm ) knockout mice, which develop thymic lymphomas at an early age. They found that ablating Cblb delayed or prevented the onset of lymphomas. Loeser and colleagues induced skin tumours in mice through UVB irradiation and found that Cblb−/− mice showed a strikingly reduced cancer susceptibility. Depletion of CD8+ T cells from UVB-irradiated Cblb−/− mice that had previously not developed cancer caused the rapid onset of fast-growing tumours, ruling out the possibility that Cblb ablation might reduce tumorigenesis through other mechanisms.

Although Cblb inactivation in CTLs seems to be a promising strategy for cancer immunotherapy, potential side effects such as increased susceptibility to autoimmune disease could limit its use and should be considered.