Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma
Melody Abikhair Burgo, Nazanin Roudiani, Jie Chen, Alexis L. Santana, Nicole Doudican, Charlotte Proby, Diane Felsen, John A. Carucci
Melody Abikhair Burgo, Nazanin Roudiani, Jie Chen, Alexis L. Santana, Nicole Doudican, Charlotte Proby, Diane Felsen, John A. Carucci
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Research Article Dermatology Transplantation

Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma

Abstract

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.

Authors

Melody Abikhair Burgo, Nazanin Roudiani, Jie Chen, Alexis L. Santana, Nicole Doudican, Charlotte Proby, Diane Felsen, John A. Carucci

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Figure 1

IL-22 treatment causes the greatest proliferative response in the least aggressive cell lines and signals via JAK1 and STAT1/3.

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IL-22 treatment causes the greatest proliferative response in the least ...
(A) Five human squamous cell carcinoma (SCC) cell lines with increasingly aggressive properties (A431 and T1, nonmetastatic; T8 and MET1, aggressive primary SCC that metastasized; MET4, metastatic deposit of MET1 primary) were studied. A proliferation assay of serum-starved A431 cells was performed to compare IL-22 treatment (100 ng/ml) with serum replacement (10% FBS) in each cell line, and growth curves were constructed. Images show the A431 cell response to IL-22 and 10% FBS (original magnification, ×10). (B) PCR for IL-22 receptor complex expression on mRNA extracted from each cell line. (C) Proliferation assay of all SCC cell lines in full growth media (10% FBS) comparing treatment with 50 ng/ml cyclosporin A (CSA), 100 ng/ml IL-22, and a combination of both. (D) A431 cells were treated with IL-22 (100 ng/ml) for 15, 30, and 60 minutes. Cell counts and Western blot for STAT3 phosphorylation at each time point are shown. (E) PCR of IL-22–treated A431 cells examining expression of genes downstream of IL-22. Data represent the mean of 3 experiments ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, determined by 1-way ANOVA with Dunnett’s multiple comparisons test, as compared with each sample’s respective control.