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Knock-out study shows how some white blood cells regulate skin cancer

A type of white blood cell that is found in the skin and assists in the body’s immune response also helps prevent skin cancer, Yale researchers have found.

Gamma-delta T cells play a major role in local immunity and “are likely to be crucial to an early defense against skin cells that have recently transformed to a premalignant or malignant state,” said Michael Girardi, M.D., assistant professor of dermatology. Girardi, primary author of a paper on the findings published in Science in September, was part of a team that included colleagues at Guy’s King’s St. Thomas Medical College in London. The team genetically engineered mice that were incapable of producing gamma-delta T cells, then exposed the knock-out mice to three different models of skin cancer.

In one model, tumor cells were injected into the skin. In another, a carcinogen was injected into the skin. For the third, carcinogens were repeatedly painted onto the skin. This last model most closely resembles cancer development in humans because it mimics repeated exposures that progress from a benign thickening of tissue to premalignant papilloma to carcinoma formation.

Girardi and his team found that, in all three models, the absence of gamma-delta T cells resulted in a higher level of skin cancer formation. In the third model, however, another type of T cell, alpha-beta, contributed to skin cancer development and progression. “There appears to be a yin-yang contribution by alpha-beta T cells to skin cancer, in that they can act in both the defense against and the promotion of carcinoma,” Girardi said.

Gamma-delta T cells work by expressing a protein, NKG2d, which binds to a molecule that is expressed by tumor cells. Once the molecule, Rae-1, is engaged by the NKG2d protein, gamma-delta T cells can kill the tumor cell. Rae-1 is expressed only in skin cells that have been exposed to chemical carcinogens that stimulate the transition to cancer. “This is an initial and important distress signal to the local T cells, and to some other cells of the immune system, that things are wrong,” Girardi said.