Cytotoxic T lymphocytes (CTLs) are key mediators of the host response against tumours, but, unfortunately, several hurdles limit their effective use in cancer immunotherapy. For example, to be fully activated, T cells require signals through both the T-cell receptor (TCR) and co-stimulatory receptors such as CD28, but many tumours lack expression of ligands for CD28. Two groups now independently report that deleting the gene encoding the E3 ubiquitin ligase Casitas B-lineage lymphoma B (CBL-B), which results in T-cell activation independent of CD28 co-stimulation, protects mice against different types of transplanted and spontaneous tumour.

Previous work showed that Cblb−/− T cells can be activated independently of CD28 signalling, and this prompted Chiang et al. to study in detail the effect of CBL-B depletion on the activity of CTLs. Following TCR stimulation, Cblb−/−CD8+ T cells, compared with wild-type cells, had increased proliferation and cytokine secretion 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 results in the suppression of the CTL antitumour response. Interestingly, Loeser and colleagues showed that Cblb−/−CD8+ T cells are also partially resistant to suppression mediated by regulatory T cells.

To test the effect of Cblb deletion on the antitumour response in vivo, Chiang and colleagues injected Cblb−/− mice subcutaneously with weakly immunogenic and highly immunogenic cells from a mouse thymoma that does not express co-stimulatory molecules. Compared with wild-type mice, the lack of Cblb in these mice prevented or attenuated tumour growth, regardless of the intrinsic immunogenicity of the tumour.Tumour rejection proved to be independent of CD28 co-stimulation, as 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, expressing the E6 and E7 human papilloma virus 16 oncoproteins. Both groups showed that tumour rejection in Cblb−/− mice was indeed mediated by CD8+ T cells and that adoptively transferred CD8+ T cells from these animals induced rejection of established tumours in recipient mice, although it is not clear whether their cytotoxic activity is required.

So, does CBL-B deficiency 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 deleting Cblb delayed or prevented the onset of lymphomas in these mice. Loeser and colleagues induced skin tumours in mice through UVB irradiation and found that Cblb−/− mice showed a strikingly reduced cancer susceptibility compared with control animals. Depletion of CD8+ T cells from the UVB-exposed Cblb−/− mice that had not previously developed cancer caused the rapid onset of fast-growing tumours, which rules out the possibility that CBL-B might reduce tumorigenesis through other mechanisms.

Although ablation of Cblb 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.