Vaccines and agents that target the tumour vasculature are two of the most attractive approaches to treating cancer. The heat-shock protein calreticulin (CRT) has been shown to combine the best of both worlds, having both immunogenic and anti-angiogenic effects. In the September issue of The Journal of Clinical Investigation, Cheng et al. report that this dual-function molecule prevents tumour growth in mice.

CRT is a Ca2+-binding protein of the endoplasmic reticulum that facilitates MHC class I antigen processing. When coupled to tumour antigen, CRT enhances the cytotoxic T-cell response against tumours, indicating its potential to increase vaccine efficiency. Remarkably, CRT has also been reported to be an endothelial-cell inhibitor that prevents angiogenesis and tumour development.

But does this protein have any effect on tumour growth in vivo? To test this, Cheng et al. created a DNA vaccine that linked the gene that encodes CRT to that of the human papillomavirus oncoprotein E7. Vaccination of mice with DNA that encodes the CRT–E7 fusion significantly enhanced the E7-specific cytotoxic T-cell response, and also induced production of antibodies against the antigen. Furthermore, CRT–E7 protected mice against the E7-expressing tumour cell line TC-1 when mice were immunized either before or after tumour development. Fusion of CRT to E7 was required for immunity, as CRT DNA that was simply mixed with E7 DNA did not enhance E7 immunogenicity.

Did the therapeutic effect of the CRT-containing construct arise from its immune-activating function, or from its anti-angiogenic function? The authors examined the effects of CRT/E7 vaccination in mice that were depleted of both cytotoxic and helper T cells. These mice were still protected from tumour growth, indicating that CRT can act independently of T cells. Furthermore, examination of pulmonary tumours grown in the mice revealed a reduction in microvessel density after CRT treatment, indicating a reduction in tumour angiogenesis.

The vaccine, however, was not as effective in immunodepleted mice as it was in immunocompetent ones, indicating that a combination of the immunological and antiangiogenic functions of CRT is required to generate the most potent antitumour effect. In the future, this approach might be applied to other cancer systems, as CRT could be linked to other known tumour antigens to increase their immunogenicity, as well as reduce tumour angiogenesis.