Immune Cells Contribute to Skin Cancer

Fran Harris | fran.harris@yale.edu November 3, 2014

The skin is constantly bombarded with harmful chemicals and rays from the environment. Despite being a formidable first line of defense against the outside world, skin cells are still unarmed against certain chemicals that cause genetic mutations, resulting in cancer.  A very common carcinogenic class of chemicals is polyaromatic hydrocarbons (PAHs), which are present in air pollution, tobacco smoke, broiled meats, and the environment. Previous research has focused on the effect of PAHs on the mutating skin cells directly. However, Yale Professor of Dermatology Michael Girardi’s research explores the idea that the problem might be in the skin’s line of defense, the immune system.

Specifically, Girardi’s research focuses on the role of a specific immune cell in the skin, the Langerhans cell, in the origin of cutaneous squamous cell carcinomas (SCC), a form of skin cancer. Langerhans cells are a type of dendritic cell, which is an antigen-presenting immune cell. They ingest invading organisms and show an identifying molecule of that organism to other immune cells so that the pathogen can be targeted and attacked. Furthermore, one of the many secondary functions of Langerhans cells is to catabolize harmful toxins into innocuous products, thereby protecting the skin.

Langerhans cells (blue) with extended dendrites adjacent to keratinocytes. The red represents the DNA damage in the keratinocytes.

Langerhans cells (blue) with extended dendrites adjacent to keratinocytes. The red represents the DNA damage in the keratinocytes.

However, in the case of SCC, these breakdown products may not be so harmless. Previously published research from the Girardi lab showed that mice lacking Langerhans cells were virtually resistant to SCC induced by PAHs. This protection occurred because although the Langerhans cells metabolized the PAHs as they would any toxin, the products of the PAHs were actually more likely to mutate the DNA of the skin cells than the original PAHs.

Girardi’s latest research tries to explain this defective waste management. He hypothesized that the ratio of two forms of the particular enzyme that breaks down PAHs (CYP1A1 and CYP1B1) is responsible for the Langerhans cells producing harmful products. The two forms of the enzyme are in both skin cells (specifically keratinocytes) and Langerhans cells, but CYP1B1 is significantly more prevalent in the Langerhans cells than in the keratinocytes.

To test this hypothesis, the cancer-resistant mice lacking Langerhans cells from the lab’s previous work were repopulated with different types of Langerhans cells. Mice that were repopulated with normal Langerhans cells gained susceptibility to the cancer, while mice that were repopulated with Langerhans cells lacking CYP1B1 were significantly more resistant to the cancer. However, some mice with Langerhans cells lacking CYP1B1 still developed SCC, leading the team to conclude that the enzymatic pathway is the primary but not only mechanism by which the Langerhans cells can contribute to the initiation of SCC.

The discovery of a mechanism of cancer induction in Langerhans cells has many far-reaching implications. According to Girardi, one key takeaway is that “cells that don’t become mutated can play a crucial role in the mutation of cells nearby.” He also suggested that these findings “might be a good model for cancers in other epithelial tissues which can be more deadly,” such as lung and liver cancers. Discovering the immune system’s involvement in skin cancer shows that we may have been looking in the wrong place to find the origins of many other cancers all along.