244 Transplant immunosuppression drives catastrophic carcinomatosis through IL 22

Organ transplant recipients (OTRs) treated with immunosuppressive agents including Cyclosporine A (CSA) often develop catastrophic SCC, characterized by multiple primary tumors, extensive body surface area involvement or metastases. At present, there are no curative systemic therapies for OTRs with catastrophic SCC. In this study, we examined links between CSA, IL-22 and SCC in patients, SCC cell lines and in mice with Ultraviolet (UV) light-induced SCC. Eighteen of 114 OTRs developed catastrophic SCC, which was strongly associated with CSA treatment. In vitro, we found that CSA drives T cell polarization towards IL-22 producing T22 cells, and treatment with CSA increased IL-22 receptor in SCC cells. SCC tissue from OTRs showed increased expression of IL-22RA1 compared to immune-competent SCC. CSA potentiated the rescue by IL-22 of serum-starved SCC cells; treatment of SCC cells with IL-22 and CSA increased both their migratory and invasive capacity. In a UV-induced model of SCC in SKH-1 immunocompetent mice, treatment with anti-IL-22 antibody reduced tumor size and overall tumor burden. Our findings indicate that catastrophic SCC in transplant recipients is associated with CSA use, which may be acting by favoring T22 polarization. Since anti-IL-22 antibody administration decreased tumor number and tumor burden in mice in vivo, blockade of the IL-22 axis may be developed as a viable therapeutic option for inoperable catastrophic SCC.