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 recognized 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 tumor 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 tumor cells (i.e. immune-independent). Using customized 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. Short-term contact hypersensitivity responses (CHS) to OVA were abrogated in both rapamycin and tacrolimus-treated mice. However, prolonging the challenge phase enhanced the long-term CHS response in rapamycin-treated but not in tacrolimus-treated mice compared to normal feed controls. This enhanced response was correlated with an increased number of effector memory CD8+ T-cell population in the challenged ear skin. Using established chronic UV dosing schedules for SCC development in HPV38 E6E7 mice, tumor samples along with surrounding UV-exposed skin and fur-covered UV-protected skin samples were analyzed with FACs under the influence of these drugs. Preliminary data suggests that the formation of resident-memory CD8+ T-cells may be favored when treated with rapamycin, as higher percentages of CD8+ T-cells were present in the lesions of rapamycin-treated mice compared to tacrolimus and controls. In addition, LC-MS/MS analysis indicated that the concentration of rapamycin in the skin was significantly lower when compared to tacrolimus, whilst clinically relevant immunosuppressive concentrations of both drugs were maintained in the blood and kidneys. Through this project, we will expand our knowledge base regarding mechanisms of SCC formation in immunosuppressed patients.
Citation Format: Ji-Won Jung, Paul J. Taylor, Fiona Simpson, Ian H. Frazer, James W. Wells. The impact of rapamycin and tacrolimus treatment on resident CD8+ T-cell populations in cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B055.
- ©2016 American Association for Cancer Research.