Imiquimod induces the expression of E-selectin (yellow) on blood vessels in skin tumors.

Like a tourist without a map, tumor-fighting T cells have a hard time finding their destination without directions. According to Clark et al. (page 2221), dismantling these directions helps skin cancer cells hide from killer T cells.

To enter the skin, T cells must grab on to the adhesive molecule E-selectin, which is expressed on the endothelial cells lining blood vessels in the skin. The authors now find that many of the vessels in skin cancer lesions lack E-selectin, causing beneficial T cells to pass by unaware. The tumors were instead populated by suppressive regulatory (T reg) cells, perhaps coaxed in by the tumor to safeguard against killer cells that somehow gain access. Both tactics have also been seen in other types of human cancer.

Reversing the suppressive effect of T reg cells is one of the beneficial effects of topical immune-stimulating drugs like the TLR agonist imiquimod, which is effective in treating certain types of skin cancer. Indeed, Clark et al. found that imiquimod treatment reduced both the percentages and function of tumor-infiltrating T reg cells. To the authors' surprise, the drug also induced E-selectin expression on tumor vessels, restoring T cell road signs and allowing killer T cells to invade the tumor.

How tumor cells turn off E-selectin and how imiquimod turns it back on are not yet known, but both effects required neighboring antigen-presenting cells (APCs) in the tumor. After imiquimod treatment, most APCs were mature dendritic cells—the most potent T cell stimulators. The effects of topical imiquimod on T reg cells are temporary, but may last just long enough to allow killer T cells to destroy the tumor without throwing off the normal balance of T cells in the skin. RB