Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22
Melody Abikhair, … , Diane Felsen, John A. Carucci
Melody Abikhair, … , Diane Felsen, John A. Carucci
Published June 2, 2016
Citation Information: JCI Insight. 2016;1(8):e86434. https://doi.org/10.1172/jci.insight.86434.
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Research Article Dermatology Transplantation

Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22

Abstract

Immune-suppressed organ transplant recipients (OTRs) can develop catastrophic squamous cell carcinoma (SCC), characterized by multiple primary tumors, extensive body surface area involvement, or metastases. There are currently no curative systemic therapies available. We previously showed that IL-22 enhances SCC proliferation. Herein, we examined links between cyclosporine (CSA), IL-22, and SCC in patients, cell lines, and mice with UV light–induced SCC. Eighteen of 114 OTRs developed catastrophic SCC, which was strongly associated with CSA treatment. We found that CSA drives T cell polarization toward IL-22–producing T22 cells, and CSA treatment increased IL-22 receptor in SCC cells. SCC tissue from OTRs showed increased expression of IL-22RA1. CSA potentiated 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 number and tumor burden. We found that catastrophic SCC in OTRs 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 vivo, blockade of the IL-22 axis may be developed as a viable therapeutic option for catastrophic SCC.

Authors

Melody Abikhair, Hiroshi Mitsui, Valerie Yanofsky, Nazanin Roudiani, Channa Ovits, Teddy Bryan, Tatiana M. Oberyszyn, Kathleen L. Tober, Juana Gonzalez, James G. Krueger, Diane Felsen, John A. Carucci

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Figure 1

CSA favors IL-22 response and effects in SCC.

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CSA favors IL-22 response and effects in SCC. (A) Treatment of A431 squa...
(A) Treatment of A431 squamous cell carcinoma (SCC) cells with IL-22 results in significantly increased proliferation, shown at ×4 magnification; proliferation is further amplified with cyclosporine A (CSA) and IL-22 in combination. Data represent mean of 3 experiments ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001 determined by one-way ANOVA with Dunnett’s multiple comparisons test. (B) Representative dot plot analysis of IFN-γ, IL-4, IL-17, and IL-22 expression in CD4+ and CD8+ T cells with and without CSA. Numbers indicate percent gated cells. Percentage change in cytokine expression with CSA treatment is shown below the plots. Data represent mean of 3 experiments ± SEM. (C) IL10RB and IL22RA1 receptor expression in patient tissue samples from tumor (SCC) and adjacent non–tumor-bearing skin (S Adj), as well as transplant patient tumor samples with catastrophic outcomes (TSCC) and adjacent non–tumor-bearing skin (T Adj) as detected by RT-PCR and normalized to Keratin14 to account for variations in epithelial tissue between the samples. Data represent mean of 5 experiments ± SEM. *P < 0.05 and **P < 0.01 determined by one-way ANOVA with Tukey’s multiple comparisons test. (D) CSA induces IL-22 receptor subunit expression in A431 SCC cells in vitro. Data represent mean of 3 experiments ± SEM. *P < 0.05 determined by one-way ANOVA with Dunnett’s multiple comparisons test.