Chennareddy Sumanth, Rindler Katharina, Ruggiero John R, Alkon Natalia, Cohenour Emry R, Tran Sophia, Weninger Wolfgang, Griss Johannes, Jonak Constanze, Brunner Patrick M
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Br J Dermatol. 2025 Jan 24;192(2):269-282. doi: 10.1093/bjd/ljae313.
Malignant clones of primary cutaneous T-cell lymphomas (CTCL) can show a CD4+, CD8+ or T-cell receptor (TCR)-γδ+ phenotype, but their individual impact on tumour biology and skin lesion formation remains ill defined.
To perform a comprehensive molecular characterization of CD4+ vs. CD8+ and TCR-γδ+ CTCL lesions.
We performed single-cell RNA sequencing (scRNAseq) of 18 CTCL skin biopsies to compare classic CD4+ advanced-stage mycosis fungoides (MF) with TCR-γ/δ+ MF and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (Berti lymphoma).
Malignant clones of TCR-γ/δ+ MF and Bertilymphoma showed similar clustering patterns distinct from CD4+ MF, along with increased expression of cytotoxic markers such as NKG7, CTSW, GZMA and GZMM. Only advanced-stage CD4+ MF clones expressed central memory T-cell markers (SELL, CCR7, LEF1), alongside B1/B2 blood involvement, whereas TCR-γδ+ MF and Berti lymphoma harboured a more tissue-resident phenotype (CD69, CXCR4, NR4A1) without detectable cells in the blood. CD4+ MF and TCR-γδ+ MF skin lesions harboured strong type 2 immune activation across myeloid cells, while Berti lymphoma was more skewed toward type 1 immune responses. Both CD4+ MF and TCR-γδ+ MF lesions showed upregulation of keratinocyte hyperactivation markers such as S100A genes and KRT16. This increase was entirely absent in Berti lymphoma, possibly reflecting an aberrant keratinocyte response to invading tumour cells, which could contribute to the formation of the typical ulceronecrotic lesions within this entity.
Our scRNAseq profiling study reveals specific molecular patterns associated with distinct CTCL subtypes.
原发性皮肤T细胞淋巴瘤（CTCL）的恶性克隆可表现为CD4 +、CD8 +或T细胞受体（TCR）-γδ +表型，但其对肿瘤生物学和皮肤病变形成的个体影响仍不明确。
对CD4 +与CD8 +以及TCR-γδ + CTCL病变进行全面的分子特征分析。
我们对18例CTCL皮肤活检组织进行了单细胞RNA测序（scRNAseq），以比较经典CD4 +晚期蕈样肉芽肿（MF）与TCR-γ/δ + MF以及原发性皮肤CD8 +侵袭性亲表皮细胞毒性T细胞淋巴瘤（伯蒂淋巴瘤）。
TCR-γ/δ + MF和伯蒂淋巴瘤的恶性克隆显示出与CD4 + MF不同的相似聚类模式，同时细胞毒性标志物如NKG7、CTSW、GZMA和GZMM的表达增加。只有晚期CD4 + MF克隆表达中枢记忆T细胞标志物（SELL、CCR7、LEF1），同时伴有B1/B2血液受累，而TCR-γδ + MF和伯蒂淋巴瘤具有更多组织驻留表型（CD69、CXCR4、NR4A1），血液中未检测到细胞。CD4 + MF和TCR-γδ + MF皮肤病变在髓系细胞中具有强烈的2型免疫激活，而伯蒂淋巴瘤更倾向于1型免疫反应。CD4 + MF和TCR-γδ + MF病变均显示角质形成细胞过度激活标志物如S100A基因和KRT16上调。伯蒂淋巴瘤中完全没有这种增加，这可能反映了角质形成细胞对侵袭性肿瘤细胞的异常反应，这可能导致该实体中典型的溃疡坏死性病变的形成。
我们的scRNAseq分析研究揭示了与不同CTCL亚型相关的特定分子模式。
