Allergic contact dermatitis (ACD) is a common skin inflammatory condition with rapidly rising prevalence among industrial nations in recent decades. Acute ACD is characterized by an intense skin rash and itching that develops at the site of exposure to contact allergens like nickel in about 20% of general population. Acute ACD is known to have tumor-suppressing effects in the skin, which has led to its use for the treatment of warts and skin cancers. However, the effects of chronic ACD on skin cancer have not been fully investigated. Implantable medical devices such as orthopedic, dental, and cardiac implants are a source of chronic ACD. These devices are being increasingly used in medical practice, which highlights the importance of research on chronic ACD to better treat this condition and prevent its associated adverse events. In a recent report, we found that chronic ACD to an orthopedic metal implant led to an invasive skin cancer in a patient. To demonstrate a causal relationship, we used the standard mouse model of contact hypersensitivity and showed that chronic application of a contact allergen to carcinogen-treated skin led to the development of aggressive skin cancers in the animals. The chronic ACD-associated inflammation was required for the skin cancer development. Importantly, we found a similar tumor-promoting inflammatory environment surrounding the skin cancer in our patient. These findings highlight a fundamental question: how does an anti-tumor immune response turn into a pro-tumor immune environment in its chronic phase? In order to address this question and determine the mechanism of tumor promotion by chronic ACD, I hypothesized that (a) skin-derived factors mediate the transition from anti-tumor skin inflammation in acute ACD to pro-tumor skin inflammation in chronic ACD, and (b) the tumor-promoting immune environment in chronic ACD is mediated by the interactions between several groups of immune cell types. To test these hypotheses, I propose to (1) determine the mechanism that mediates the transition from tumor-suppressing immune response in acute ACD to tumor- promoting immune environment in chronic ACD, and (2) Determine the mechanism of tumor promotion in chronic ACD. The outcome of this research will provide a mechanistic insight into the role of ACD in skin cancer development. Considering the role of chronic inflammation in promoting cancer development in several organs, the understanding of how chronic ACD promotes skin cancer will be highly applicable in blocking the tumor-promoting effects of chronic inflammation in the skin and other organs.
This proposal is founded on a critical discovery that chronic allergic contact dermatitis (ACD) is a potent tumor- promoter in the skin. The overall aim of this research is to determine the mechanism that mediates the development of chronic ACD and the factors that generate its tumor-promoting effects. The outcomes of this study will guide the path to better treatment for chronic ACD and optimal therapeutic use of contact allergens in immune-based treatments for skin cancers, which affect a large number of individuals in United States and around the world.
