Defining the role of the IgE-Fc epsilon receptor-1 immune surveillance axis in human cutaneous squamous cell carcinoma

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Context of research:Skin cancer is the most common human cancer and cutaneous squamous cell carcinoma (cSCC) is the second most common form. cSCC is caused mainly by ultraviolet radiation (UV) from sun exposure. At least 30,000 new cases occur every year in the UK and cSCC is more common in patients with compromised immune systems. Most cSCC are treated surgically, but this may cause significant problems, given that 70% are on cosmetically sensitive head and neck locations and many patients develop more than one cSCC. Advanced (metastatic) cSCC with spread to lymph nodes or internal organs occurs in up to 5% and current treatments have poor responses, although recent evidence suggests immunotherapy may be promising. Nonetheless, advanced cSCC remains an area of important unmet clinical need. In previous research, we showed that genetic damage is higher in cSCC than in almost any other cancer (probably because UV is very mutating) and also that immune genes are particularly mutated in cSCC at high risk of metastasis, including the immune gene Fc epsilon receptor 1 (FCER1). We showed that in response to skin damage (e.g. UV or chemicals), the antibody IgE is released by cells and this results in increased numbers of immune cells containing the protein FceR1 which act to defend the body against skin cancer. This interaction affects how the immune system suppresses skin cancer in mice: when the IgE-FceRI interaction is reduced, skin cancer risk is increased.Aims and methods:We will investigate how IgE-FceRI interactions control cSCC development and whether this affects risk of metastasis. We will first examine which cSCC immune cells carry the receptor by a detailed analysis of fresh tumours using a technique which allows us to identify the exact type of immune cells present and whether or not they carry FceRI (FceRI+). We will particularly look for differences between low-risk, high-risk and metastatic cSCC. We will then investigate the precise location of FceRI+ immune cells in tumours as this may provide further information on their role in cSCC. We will use a technique in which whole tumour sections are examined and the exact location of cells can be identified. These results will be confirmed in a larger series of cSCC using antibodies to FceRI+ cells. We will ask whether the presence and location of FceRI+ cells are associated with metastatic risk and whether FceRI is a marker for increased risk. We will also test for the activity of the FceRI gene in this larger series of samples and will again investigate if this is associated with cSCC that metastasise. In the final series of experiments we will investigate whether altering IgE-FceRI interactions has an effect on cSCC growth. We will use cSCC cell lines that we have previously grown from patients and also small fresh cSCC samples and will add drugs that either block or increase IgE-FceRI interactions and see how this changes the behaviour of cancer cells. Finally, we will transplant human cSCC samples into mice, either by inserting a small piece of tumour or injecting suspensions of tumour cells into the mouse skin. Blocking and stimulating drugs will again be used to examine effects on cSCC growth and the resulting tumours will be analysed in detail for the presence of the immune cells and FceRI. Potential applications and benefits:In summary, our previous research has suggested an important role for IgE-FceRI in cSCC. We will investigate the presence and location of FceRI-expressing cells in cSCC and whether this influences the risk of tumours progressing. We will also examine whether blocking or stimulating this interaction has an effect on tumour growth. Ultimately, this research will improve our understanding of how cSCCs develop. It may also provide important markers for predicting which cSCC are at high risk of metastasis. Finally, it may also provide important directions for developing new treatments suitable for advanced cSCC.