Skin cancer is one of the most prevalent cancers in the world. The highest incidence rate of skin cancer is reported in Australia, where two out of every three people are likely to be diagnosed in their lifetime. Recurrent and prolonged exposure to ultraviolet (UV) radiation from sun plays a crucial role in the initiation, development, and perpetuation of squamous cell carcinoma (SCC) and other non-melanoma cancers. UV causes an array of biological implications including damage to DNA, proteins, lipids, and the suppression of the immune system. Unlike immunosuppressive drugs, UV induces immunosuppression in an antigen-specific manner via the induction of regulatory T cells (Tregs). UV-induced Tregs express CD4, CD25, CTLA-4, and Foxp3 and secrete the cytokine interleukin (IL)-10 upon activation. We hypothesise that different approaches for the manipulation of Tregs could be effective in preventing or treating cutaneous malignancies. In this study, we will establish different UV regimens ranging from short to medium term-exposure and investigate the impact on the phenotypic and functional properties of Tregs in skin. Next, we will determine whether immunomodulation strategies such as depletion of Tregs and/or administration of IL-12 and CTLA-4 antibody can breach suppressive mechanisms induced by UV. Finally, we will investigate the propensity of mice treated with different UV-treatment regimens to develop SCC tumours following SCC cell line challenge and use this model to study the effect of our immunomodulation strategies on SCC tumour establishment and growth.