Boosting adhesion molecule expression in tumor blood vessels (red) allows more tumor-killing T cells (green) to gain access.

On page 2125, Quezada et al. find that big tumors might evade T cell destruction by shutting down adhesion molecules.

Tumor-fighting T cells work better when suppressive regulatory T (T reg) cells are not lurking. But treatments that either deplete T reg cells or boost anti-tumor T cell activity aren't enough to destroy tumors, as Quezada et al. now show.

As seen in other tumor models, skin tumors in mice were destroyed when the group depleted T reg cells before tumor implantation. But if they depleted T reg cells after tumors had already developed, the treatment failed, even if the animals were given T cell–boosting drugs. Plenty of potential tumor-killing T cells were available, but they did not seem to infiltrate the tumors.

Small tumors, at least, were sensitive to T cells. When T reg cell depletion was combined with T cell–boosting drugs, small, newly implanted tumors were destroyed. But well-established tumors resisted the effects of this regimen.

Established tumors, the group found, had fewer adhesion molecules on surrounding blood vessels. To determine whether these adhesives might help T cells invade bigger tumors, the group induced adhesion molecules in mice using irradiation. Zapped mice that were then injected with anti-tumor T cells along with activity-enhancing drugs fought off tumors. But irradiated mice that were also injected with T reg cells put up a weak fight. How tumors dial down adhesion molecules as they grow and whether T reg cells coerce them into doing so remain to be seen.

The findings might explain why treatments that deplete T reg cells and enhance killer T cell activity haven't fared well in clinical trials. Perhaps combining them with irradiation might make them more effective.