Using in vivo experiments on mice with skin cancer, the authors observed a delay in tumour growth after combining treatment with a tumour vaccine and subsequent KINK-1 treatment. These findings present IKKβ as a potential new druggable target of the immune system that could impact the development of future cancer treatments (Cell Reports 21 578).

The immune system recognises cells that are infected by viruses, and stimulates CD8+ T cells to target and destroy them. In contrast, regulatory T cells suppress the immune response of CD8+ T cells to prevent them from targeting erroneously healthy tissue.

Cancer cells also induce an immune response from CD8+ T cells. However, they exploit immunological processes to evade this response. For instance, they capitalize on the immune suppression function of regulatory T cells and recruit them to recognise tumours as healthy tissue, which provides tumours with a "cloak of invisibility" and thus hampers the immune response.

In this context, the authors investigated the role of IKKβ in the survival of regulatory T cells and the effect of its inhibition in potentiating antitumor immune response.

Unveiling the tumours' cloak of invisibility

The study revealed that prolonged exposure to KINK-1 resulted in a 50% reduction in regulatory T cells in cell culture and in mice, while the numbers of CD8+ T cells remained unaffected.

To understand this resistance of the CD8+ T cells to KINK-1, the authors tested the role of the transcription factor NFATc1 in CD8+ T cell survival. They observed that blocking NFATc1 did not affect the survival of regulatory T cells. In contrast, CD8+ T cells started dying only after blocking NFATc1 and IKKβ in combination, further demonstrating the selective targeting of regulatory T cells with IKKβ inhibition.

Treating tumours using combined therapies

These findings led the authors to believe that selective targeting of regulatory T cells can boost the effect of CD8+ T cells in tumours. To test this idea, they implanted melanoma tumours in mice and followed a therapy protocol in which tumour vaccination was used together with KINK-1 treatment.

The authors reported a delay in tumour growth and an increase in survival time for mice treated with the combined therapy in comparison with tumour-vaccinated mice. They also concluded that vaccination was necessary to increase the number of active CD8+ T cells since IKKβ plays a role in their activation.

The study confirms the potential of combining targeted therapies with tumour vaccination to potentiate the immune response. Furthermore, it contributes to the body of research in cancer immunotherapies, in particular, to the development of immune checkpoint inhibitors, i.e., molecules such as KINK-1, whose targets regulate the immune response.