Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
J Invest Dermatol. 2024 Mar;144(3):621-632.e1. doi: 10.1016/j.jid.2023.06.212. Epub 2023 Sep 15.
Transcriptional profiling demonstrated markedly reduced type I IFN gene expression in untreated mycosis fungoides (MF) skin lesions compared with that in healthy skin. Type I IFN expression in MF correlated with antigen-presenting cell-associated IRF5 before psoralen plus UVA therapy and epithelial ULBP2 after therapy, suggesting an enhancement of epithelial type I IFN. Immunostains confirmed reduced baseline type I IFN production in MF and increased levels after psoralen plus UVA treatment in responding patients. Effective tumor clearance was associated with increased type I IFN expression, enhanced recruitment of CD8 T cells into skin lesions, and expression of genes associated with antigen-specific T-cell activation. IFNk, a keratinocyte-derived inducer of type I IFNs, was increased by psoralen plus UVA therapy and expression correlated with upregulation of other type I IFNs. In vitro, deletion of keratinocyte IFNk decreased baseline and UVA-induced expression of type I IFN and IFN response genes. In summary, we find a baseline deficit in type I IFN production in MF that is restored by psoralen plus UVA therapy and correlates with enhanced antitumor responses. This may explain why MF generally develops in sun-protected skin and suggests that drugs that increase epithelial type I IFNs, including topical MEK and EGFR inhibitors, may be effective therapies for MF.
转录谱分析表明，未经治疗的蕈样肉芽肿（MF）皮肤病变中的 I 型 IFN 基因表达明显低于健康皮肤。MF 中的 I 型 IFN 表达与光疗前抗原呈递细胞相关的 IRF5 以及治疗后的上皮细胞 ULBP2 相关，提示上皮细胞 I 型 IFN 增强。免疫染色证实，MF 中 I 型 IFN 的基础产量降低，而在光疗后应答患者中水平升高。有效的肿瘤清除与 I 型 IFN 表达增加、CD8 T 细胞更多地募集到皮肤病变以及与抗原特异性 T 细胞激活相关的基因表达有关。IFNk 是角质形成细胞来源的 I 型 IFN 诱导物，经光疗后增加，其表达与其他 I 型 IFN 的上调相关。在体外，角质形成细胞 IFNk 的缺失降低了 I 型 IFN 的基础表达和 UVA 诱导表达以及 IFN 反应基因的表达。总之，我们发现 MF 中存在 I 型 IFN 产生的基线缺陷，经光疗后得到恢复，并与增强的抗肿瘤反应相关。这可能解释了为什么 MF 通常在防晒皮肤中发展，并表明包括局部 MEK 和 EGFR 抑制剂在内的增加上皮细胞 I 型 IFNs 的药物可能是 MF 的有效治疗方法。
