Although tumour-specific T cells can be isolated from cancer patients, their ability to attack the tumour and induce regression is often impaired, possibly because tumour-antigen presentation is suboptimal. Several studies have addressed this issue by stimulating antigen-presenting cells with anti-CD40 antibodies, in conjunction with tumour-antigen immunization, to enhance weak anti-tumour T-cell responses. However, a recent study in Proceedings of the National Academy of Sciences now indicates that the anti-CD40 approach to manipulating tumour responses should be applied with caution — treatment of mice bearing melanoma tumours with anti-CD40 alone enhanced the deletion of tumour-specific CD8+ T cells.

Kedl and colleagues developed a mouse melanoma model system in which the B16 melanoma cell line transfected with an ovalbumin (OVA) peptide was injected intradermally, and CD8+ T-cell responses to the peptide were tracked using a major histocompatibility complex (MHC)-tetramer construct. Because OVA-specific CD8+ T cells — although transient and non-functional — were detected in mice challenged with the tumour alone, the authors reasoned that anti-CD40 treatment, in the absence of tumour-antigen immunization, might be sufficient to rescue the function of the tumour-specific CD8+ T cells. This approach would be beneficial because it would not be necessary to determine the specific tumour antigens for each patient. Surprisingly, anti-CD40 treatment accelerated the deletion of tumour-specific CD8+ T cells, and co-immunization with vaccinia virus expressing OVA was required to prevent this deletion.

There is a long way to go in determining the precise signals required for manipulating the immune response to tumours in vivo. This study suggests caution in the use of anti-CD40 therapy, and future work must focus on the additional signals required to induce functional T-cell responses to tumours.