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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 Interleukin-22 (IL-22). Herein, we found 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 JAK 1/2 inhibitor, Ruxolitinib. In human SCC cells, greatest proliferative response to IL-22 and CSA treatment occurred in non-metastasizing 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 to 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 STAT 1/3 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. In this study, microarray data was used to compare normal skin to immunocompetent SCC, to transplant associated SCC (TSCC)

ORGANISM(S): Homo sapiens

PROVIDER: GSE117247 | GEO | 2018/07/18

REPOSITORIES: GEO

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Project description:Hemophagocytic lymphohistiocytosis (HLH) comprises an expanding array of immune system disorders in which activated T and myeloid cells overproduce pro-inflammatory cytokines, many of which signal via the JAK/STAT pathway. Towards this end, use of the JAK1/2 inhibitor ruxolitinib has shown promising results in HLH pre-clinical and early phase clinical studies. Nevertheless, there remains concern for ruxolitinib-induced cytopenias, which are postulated to result from blockade of JAK2-dependent hematopoietic growth factors. To explore whether inhibition of JAK1, while sparing JAK2, might lessen inflammation and minimize hematologic toxicities in mouse models of HLH, we carried out experiments incorporating the JAK1 inhibitor itacitinib and the JAK2 inhibitor fedratinib. Itacitinib and fedratinib were well-tolerated and suppressed in vivo IFNg-mediated STAT1 phosphorylation. JAK1 inhibition with itacitinib lessened tissue infiltration of immune cells and significantly decreased serum cytokine levels of in a model of secondary (non-familial) HLH in which mice receive repeated doses of CpG DNA and IL-10 receptor blockade. However, its effects in a model of primary (familial) HLH where perforin-deficient (Prf1–/–) mice are infected with Lymphocytic Choriomeningitis virus (LCMV) were less pronounced. JAK2 inhibition with fedratinib exerted beneficial effects in both models, where it functioned similarly to ruxolitinib in improving cytopenias and reducing splenomegaly, hypercytokinemia and T cell IFNg production. RNA sequencing revealed that itacitinib induced only modest changes in gene expression in T and myeloid cells from LCMV-infected mice, while fedratinib downregulated pathways involved in cell proliferation, metabolism and oxidative phosphorylation. Neither drug rivaled the anti-inflammatory transcriptional changes seen with ruxolitinib. In summary, itacitinib and fedratinib are tolerated in mice models of primary and secondary HLH at or above clinically-relevant doses but exert differential effects with itacitinib showing partial disease improvement in the model of secondary HLH and fedratinib showing benefits similar to ruxolitinib in primary HLH.

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Ruxolitinib inhibits Cyclosporine-induced proliferation of cutaneous squamous cell carcinoma

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