Organ transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) development. Immunosuppressive agents, given to these patients to prevent organ rejection, are widely recognised to play a key role in the increased incidence of malignancy. However, different immunosuppressive agents, such as rapamycin and tacrolimus, which both prevent organ rejection, convey different risks of tumour formation. Using a UV-induced murine model of squamous cell carcinoma (SCC); HPV38 E6E7, we aim to determine whether these discrepancies are due to differences in the mechanism of immune suppression, in contrast to the much discussed direct effects of these drugs on tumour cells (i.e. immune-independent). Using customised rapamycin- and tacrolimus-incorporated feed to allow long-term administration, clinically relevant whole blood drug concentrations were obtained and validated using LC-MS/MS. Both systemic and local immunosuppression was functionally determined via adoptively transferred transgenic T-cell assay and skin allograft rejection profile, respectively. Notably however, preliminary data suggests phenotypic and functional differences of skin-residing T-cell subpopulations may exist when mice are treated with either rapamycin or tacrolimus, alluding to their potential role in the pathogenesis of NMSC. Using established UV dosing schedules for SCC development, the kinetics of tumour formation will be assessed under the influence of these drugs. In addition, immunosuppressant treated HPV38 E6E7 mice backcrossed onto Rag1-/- mice (lacking T and B cells) will further elucidate the contribution of these drugs in SSC development. Through this project, we will expand our knowledge base regarding mechanisms of SCC formation in immunosuppressed patients.