Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma

• Published in: JCI insight Vol. 3; no. 17
• Main Authors: Abikhair Burgo, Melody, Roudiani, Nazanin, Chen, Jie, Santana, Alexis L, Doudican, Nicole, Proby, Charlotte, Felsen, Diane, Carucci, John A
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 06.09.2018
• Subjects: Animals; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor - drug effects; Cell Proliferation - drug effects; Cyclosporine - adverse effects; Disease Models, Animal; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Heterografts - drug effects; Heterografts - pathology; Humans; Interleukin-22; Interleukins - metabolism; Interleukins - pharmacology; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Mice; Mice, Nude; Nitriles; Organ Transplantation; Pyrazoles - pharmacology; Pyrimidines; Receptors, Interleukin - metabolism; Signal Transduction - drug effects; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - pathology; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transplantation; Organ transplantation; Drug therapy; Dermatology; Skin cancer
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.120750

Organ transplant recipients (OTRs) on cyclosporine A (CSA) are prone to catastrophic cutaneous squamous cell carcinoma (SCC). Allograft-sparing, cancer-targeting systemic treatments are unavailable. We have shown increased risk for catastrophic SCC in OTRs via CSA-mediated induction of IL-22. Herein, we found that CSA drives SCC proliferation and tumor growth through IL-22 and JAK/STAT pathway induction. We in turn inhibited SCC growth with an FDA-approved JAK1/2 inhibitor, ruxolitinib. In human SCC cells, the greatest proliferative response to IL-22 and CSA treatment occurred in nonmetastasizing lines. IL-22 treatment upregulated JAK1 and STAT1/3 in A431 SCC cells. JAK/STAT pathway genes were highly expressed in tumors from a cohort of CSA-exposed OTRs and in SCC with high risk for metastasis. Compared with immunocompetent SCC, genes associated with innate immunity, response to DNA damage, and p53 regulation were differentially expressed in SCC from OTRs. In nude mice engrafted with human A431 cells, IL-22 and CSA treatment increased tumor growth and upregulated IL-22 receptor, JAK1, and STAT1/3 expression. Ruxolitinib treatment significantly reduced tumor volume and reversed the accelerated tumor growth. CSA and IL-22 exacerbate aggressive behavior in SCC. Targeting the IL-22 axis via selective JAK/STAT inhibition may reduce the progression of aggressive SCC in OTRs, without compromising immunosuppression.