Purpose of Review

Cutaneous T cell lymphomas (CTCLs) exhibit a wide variety of clinical features, histologic characteristics, and genetic drivers. We review novel molecular findings that inform our understanding of the pathogenesis of CTCL, with a focus on the tumor microenvironment (TME).

Recent Findings

There is increasing evidence challenging the model of T_CM:mycosis fungoides (MF) and T_EM:Sézary syndrome (SS) phenotype. Phylogenetic analysis performed using whole-exome sequencing (WES) raises the possibility that MF can arise without a common ancestral T cell clone. The detection of ultraviolet (UV) marker signature 7 mutations in the blood of patients with SS raises questions about the role of UV exposure in CTCL pathogenesis. There is also increasing interest on the role of the TME in CTCL. Existing therapies such as the RXR retinoid bexarotene and the anti-CCR4 monoclonal antibody mogamulizumab may act through the CTCL TME by impacting the CCL22:CCR4 axis, while cancer-associated fibroblasts (CAFs) in the CTCL TME contribute to drug resistance, as well as a Th2 milieu and tumor growth via secretion of pro-tumorigenic cytokines. Staphylococcus aureus (SA) is a frequent cause of morbidity among CTCL patients. SA may positively select for malignant T cells through adaptive downregulation of alpha-toxin surface receptors and promotion of tumor growth via upregulation of the JAK/STAT pathway.

Summary

Recent molecular advancements have contributed to our understanding of the pathogenesis of CTCL and shed light into the potential mechanisms of existing therapies. Further understanding of the CTCL TME may fuel the discovery of novel therapies for CTCL.

中文翻译：

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皮肤 T 细胞淋巴瘤的新分子和生物学标志物：治疗意义

审查目的

皮肤 T 细胞淋巴瘤 (CTCL) 具有多种临床特征、组织学特征和遗传驱动因素。我们回顾了新的分子发现，这些发现使我们了解了 CTCL 的发病机制，重点是肿瘤微环境 (TME)。

最近的发现

_{越来越多的证据挑战 T CM}模型：蕈样肉芽肿 (MF) 和 T _EM：Sézary 综合征 (SS) 表型。使用全外显子组测序 (WES) 进行的系统发育分析提出了 MF 可以在没有共同的祖先 T 细胞克隆的情况下出现的可能性。在 SS 患者血液中检测到紫外线 (UV) 标志物特征 7突变，引发了关于紫外线暴露在 CTCL 发病机制中的作用的问题。人们对 TME 在 CTCL 中的作用也越来越感兴趣。RXR 类维生素 Bexarotene 和抗 CCR4 单克隆抗体 mogamulizumab 等现有疗法可能通过影响 CCL22 :CCR4通过 CTCL TME 发挥作用轴，而 CTCL TME 中的癌症相关成纤维细胞 (CAF) 有助于耐药性，以及通过分泌促肿瘤细胞因子促进 Th2 环境和肿瘤生长。金黄色葡萄球菌(SA) 是 CTCL 患者发病的常见原因。SA 可能通过适应性下调 α 毒素表面受体和通过上调 JAK / STAT 通路促进肿瘤生长来积极选择恶性 T 细胞。

概括

最近的分子进展有助于我们了解 CTCL 的发病机制，并阐明现有疗法的潜在机制。进一步了解 CTCL TME 可能会推动 CTCL 新疗法的发现。