Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma
Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma
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DOI：
10.1172/jci.insight.120750
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发表时间：
2018-09-06
期刊：
影响因子：
8
通讯作者：
Carucci, John A.
中科院分区：
文献类型：
--
作者：
Burgo, Melody Abikhair;Roudiani, Nazanin;Carucci, John A.
接受环孢素A（CSA）的器官移植受者（OTR）容易发生灾难性的皮肤鳞状细胞癌（SCC）。保留同种异体移植物、靶向癌症的系统性治疗不可用。我们已经证明，通过CSA介导的IL-22诱导，OTR中灾难性SCC的风险增加。在此，我们发现CSA通过IL-22和JAK/STAT通路诱导来驱动SCC增殖和肿瘤生长。我们反过来用FDA批准的JAK 1/2抑制剂ruxolitinib抑制SCC生长。在人SCC细胞中，对IL-22和CSA治疗的最大增殖反应发生在非转移细胞系中。IL-22处理上调A431 SCC细胞中JAK 1和STAT 1/3。JAK/STAT通路基因在CSA暴露的OTR队列肿瘤和转移风险高的SCC中高度表达。与免疫活性的SCC相比，与先天免疫、DNA损伤反应和p53调控相关的基因在SCC和OTR中的表达存在差异。在植入人A431细胞的裸鼠中，IL-22和CSA治疗增加了肿瘤生长并上调了IL-22受体、JAK 1和STAT 1/3表达。Ruxolitinib治疗显著减小了肿瘤体积并逆转了加速的肿瘤生长。CSA和IL-22加剧了SCC中的攻击行为。通过选择性JAK/STAT抑制靶向IL-22轴可能会减少OTR中侵袭性SCC的进展，而不会影响免疫抑制。
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.