IL-13 Signaling in CD30(+) Cutaneous Lymphoproliferative Disorders
IL-13 Signaling in CD30(+) Cutaneous Lymphoproliferative Disorders
复制标题
CD30( ) 皮肤淋巴增殖性疾病中的 IL-13 信号转导
DOI：
10.1016/j.jid.2020.09.012
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发表时间：
2021
影响因子：
6.5
通讯作者：
Kadin Marshall E.
中科院分区：
文献类型：
--
作者：
Wen Yujie;Sun Jingru;Yi Shengguo;Gao Yumei;Kouttab Nick;Morgan John;Wang Yang;Kadin Marshall E.
CD30+ 皮肤淋巴增殖性疾病 (CLPD) 是第二常见的皮肤 T 细胞淋巴瘤 (CTCL)，约占所有 CTCL 的 25% (Willemze et al., 2019)。该组代表一系列疾病，从淋巴瘤样丘疹病到原发性皮肤间变性大细胞淋巴瘤 (pcALCL)。我们最近发表的文章表明，SATB1 高表达定义了 pcALCL 的亚型，其具有 T 辅助型 (Th) 17 极化、显着的表皮增生、粒细胞浸润增加以及对治疗的更好反应 (Sun et al., 2018)。 SATB1 编码特殊的富含 AT 序列结合蛋白 1，是一种胸腺细胞特异性染色质组织者，在 T 细胞激活过程中调节大量基因的表达 (Naik 和 Galande，2019)。在这项研究中，我们发现 SATB1+ 病例中包含 IL-13 信号通路的基因出人意料地高表达。 Th2 细胞因子 IL-13 调节淋巴细胞增殖和活化，并参与蕈样肉芽肿和 Sézary 综合征的发病机制（Gaydosik 等，2020；Geskin 等，2015）。 Th2-Th17 双极化 Th 细胞已在炎症 T 细胞中报道过 (Wang et al., 2010)，但此前在恶性 T 细胞中尚未有报道。为了进一步探讨IL-13信号通路在CD30+ CLPD中的作用，我们研究了Mac细胞系和37个CD30+ CLPD临床样本中SATB1和IL-13信号通路的表达，并探讨了其潜在的临床意义。发现Mac1和Mac2A细胞系是研究CD30+ CLPD中IL-13信号的有用模型。它们是由一名从淋巴瘤样丘疹病进展为 pcALCL 的患者建立的。 Mac1 细胞源自循环的 Sézary 样细胞，而 Mac2A 细胞则在 2 年后源自间变性皮肤肿瘤（Davis 等，1992）。我们之前表明，两种细胞系均高度表达 SATB1，其中 Mac2A 的 SATB1 表达水平高于 Mac1 (Wang et al., 2014)。在pcALCL的临床样本中，与SATB1-病例相比，SATB1+病例中IL-13信号通路的基因（包括IL-13、IL-13Ra1、IL-13Ra2和IL-4Ra）富集（图1a，从我们之前的RNA测序结果中提取的数据）（Sun等人，2018）。 Mac2A 来源的原发性皮肤肿瘤显示表皮增生和中性粒细胞和嗜酸性粒细胞浸润，并含有具有 Th17 表型的间变性肿瘤细胞，包括 RORγt、IL-17F 和 IL-22，与之前描述的 SATB1+ 表型一致。肿瘤细胞还表现出 Th2 表型，包括 GATA3、IL-4 和 IL-13 表达（图 1 b）。 ELISA显示Mac2A细胞分泌IL-13、IL-17A、IL-17F和IL-22，而Mac1细胞分泌IL-17A和IL-22，但仅分泌低水平的IL-13（图1c）。当我们在Mac1细胞中过表达SATB1时，IL-13表达水平上调，表明SATB1正向调节IL-13的表达（图1d）。通过RNA测序和流式细胞术，发现与其他间变性大细胞淋巴瘤和CTCL细胞系相比，IL-13信号受体在Mac1/2A细胞上高表达，包括IL-4Ra和IL-13Ra1（图1 e和f）。细胞系和原发性肿瘤细胞均高度表达磷酸化信号转导器和转录激活剂6 (pSTAT6)（图1g）。这些数据表明，SATB1 可以调节 IL-13 并激活 Mac 细胞和 SATB1+ CD30+ CLPD 中的 IL-13/信号转导器和转录 6 信号通路激活剂。
CD30+ cutaneous lymphoproliferative disorders (CLPDs) are the second most common group of cutaneous T-cell lymphomas (CTCLs), comprising about 25% of all CTCLs (Willemze et al., 2019). This group represents a spectrum of diseases, ranging from lymphomatoid papulosis to primary cutaneous anaplastic large cell lymphoma (pcALCL). Our recent publication demonstrated that high SATB1 expression defines a subtype of pcALCLs that have T helper type (Th) 17 polarization, prominent epidermal hyperplasia, increased granulocyte infiltration, and a better response to treatment (Sun et al., 2018). SATB1, encoding special AT-rich sequence-binding protein 1, is a thymocyte-specific chromatin organizer that regulates the expression of a large number of genes during T-cell activation (Naik and Galande, 2019). In this study, we found an unexpected high expression of genes comprising the IL-13 signaling pathway in SATB1+ cases. The Th2 cytokine IL-13 regulates lymphocyte proliferation and activation and is involved in the pathogenesis of mycosis fungoides and Sézary syndrome (Gaydosik et al., 2020; Geskin et al., 2015). Th2-Th17 bipolarized Th cells have been reported in inflammatory T cells (Wang et al., 2010) but not before described in malignant T cells. To further explore the role of the IL-13 signaling pathway in CD30+ CLPDs, we investigated the expression of SATB1 and the IL-13 signaling pathway in Mac cell lines and 37 clinical samples of CD30+ CLPDs and explored its potential clinical implications.Mac1 and Mac2A cell lines were found to be a useful model to study IL-13 signaling in CD30+ CLPD. They were established from a patient who progressed from lymphomatoid papulosis to pcALCL. Mac1 cells were derived from circulating Sézary-like cells and Mac2A 2 years later from an anaplastic skin tumor (Davis et al., 1992). We previously showed that both cell lines highly express SATB1, in which Mac2A shows higher SATB1 expression level than Mac1 (Wang et al., 2014). In clinical samples from pcALCLs, genes of the IL-13 signaling pathway, including IL-13, IL-13Ra1, IL-13Ra2, and IL-4Ra, were enriched in SATB1+ cases compared with SATB1–cases (Figure 1 a, data extracted from our previous RNA-sequencing result)(Sun et al., 2018). The primary skin tumor from which Mac2A was derived revealed epidermal hyperplasia and infiltration by neutrophils and eosinophils and contained anaplastic tumor cells with a Th17 phenotype, including RORγt, IL-17F, and IL-22, consistent with the previously described SATB1+ phenotype. The tumor cells also showed a Th2 phenotype, including GATA3, IL-4, and IL-13 expression (Figure 1 b). ELISA showed that Mac2A cells secrete IL-13, IL-17A, IL-17F, and IL-22, whereas Mac1 cells secrete IL-17A and IL-22 but only a low level of IL-13 (Figure 1 c). When we overexpressed SATB1 in Mac1 cells, IL-13 expression level was upregulated, indicating that SATB1 positively regulates expression of IL-13 (Figure 1 d). By RNA-sequencing and flow cytometry, IL-13 signaling receptors are found to be highly expressed on Mac1/2A cells, including IL-4Ra and IL-13Ra1, compared with other anaplastic large cell lymphoma and CTCL cell lines (Figure 1 e and f). Both cell lines and primary tumor cells highly express phosphorylated signal transducer and activator of transcription 6 (pSTAT6)(Figure 1 g). These data suggest that SATB1 can regulate IL-13 and activate the IL-13/signal transducer and activator of transcription 6 signaling pathways in Mac cells and SATB1+ CD30+ CLPDs.