Oral Presentation Australasian Society for Dermatological Research Annual Scientific Meeting 2017

The role of rapamycin in the reduction of de novo squamous cell carcinoma establishment (#4)

Gabrielle Kelly 1 , Margaret Veitch 1 , Jazmina L. Gonzalez Cruz 1 , James W Wells 1
  1. The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia

Patients receiving immunosuppressive drugs to prevent organ transplant rejection suffer a greatly increased risk of cutaneous squamous cell carcinoma (SCC) development. However, not all immunosuppressive drugs confer the same risk. Randomised, controlled trials demonstrate that switching renal transplant recipients receiving calcineurin inhibitor-based therapies to mammalian target of rapamycin (mTOR) inhibitors results in a reduced incidence of de novo SSC formation, and can even result in the regression of pre-existing premalignant lesions. However, very little is understood about the contribution played by residual immune function in this setting. We examined the hypotheses that mTOR inhibitors promote T-cell activity in the skin through the enhanced differentiation and function of CD8 memory T-cells, and that consequent CD8 T-cell function plays a key role in reducing the incidence of de novo SSC formation. Customized drug-incorporated diets were developed to allow long-term oral drug administration at clinically relevant whole blood drug target thresholds. Systemic and local immunosuppression were confirmed via the functional assessment of adoptively transferred transgenic T-cells and antigen-expressing skin graft rejection profiles, respectively. Short-term contact hypersensitivity (CHS) responses to OVA were abrogated in both rapamycin and tacrolimus-treated mice, whereas prolonging the challenge phase to permit the development of CD8 memory T-cells enhanced the long-term CHS response in rapamycin-treated mice only. An examination of patient skin confirmed an increased abundance of CD8 memory T-cells in the sun-exposed skin of renal transplant patients receiving rapamycin when compared to patients that received tacrolimus or who did not receive immunosuppressive drugs. We have now generated an adoptive transfer model of UV-induced SCC in the mouse, which we are using to define whether rapamycin requires functional T-cells to reduce the incidence of de novo SSC formation, and whether rapamycin may preserve the effector function of CD8 memory T-cells within established SCC.