The Yale team, including colleagues at Guy's King's St. Thomas Medical College in London, also found that when T cells of the alpha-beta type are selectively reduced, tumor growth is also reduced, paving the way for new drug targets for skin cancer treatment.
"Our study results add to the increasingly recognized importance of viewing the immune system from the perspective of having both a 'local' and a 'circulating' component," said primary author Michael Girardi, M.D., assistant professor of dermatology at Yale School of Medicine.
Using genetically engineered or "knockout" mice that can't produce gamma-delta T cells, Girardi and his colleagues demonstrated the role of these T cells in three different models of skin cancer: a system where tumor cells are injected into the skin; a system where a single potent chemical carcinogen (methylcholanthrene) is injected into the skin; and a system where chemical carcinogens are serially painted onto the skin. Girardi said this last model most closely emulates cancer development in human skin and other organs because it mimics the repeated exposures that lead to "multi-stage cacinogenesis," progressing from benign thickening of tissue, to pre-malignant papilloma formation, to carcinoma formation.
In all three systems, Girardi and the team found that the absence of gamma-delta T cells resulted in a higher level of skin cancer formation. Paradoxically, they also found that in the third model, the presence of alpha-beta T cells actually 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 both in the defense against and in the promotion of carcinoma," Girardi said.
The researchers showed that gamma delta T cells carry out their anti-cancer function by expressing a protein called NKG2d, which can focus in on a molecule called Rae-1, which is expressed by tumor cells. Once Rae-1 is engaged by NKG2d, the gamma-delta T cells are then able to kill the tumor cell. Girardi said that Rae-1 is not expressed in normal skin, but is displayed by skin cells that have been exposed to chemical carcinogens that stimulate the transformation into 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. "Gamma-delta T cells play a major role in local immunity and are likely crucial to an early defense against skin cells that have recently transformed to a pre-malignant or malignant state."
Other researchers on the study include Robert E. Tigelaar, Julia M. Lewis, Earl Glusac and Renata Filler of Yale's Department of Dermatology and the Yale Skin Diseases Research Core Center; David E. Oppenheim, Carrie R. Steele and Adrian C. Hayday of Guy's King's St. Thomas Medical School; and Paul Hobby and Brian Sutton of The Randall Centre for Molecular Medicine, Guy's Hospital, King's College in England.
Journal
Science