Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice [scRNA/TCR-seq]. Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice [scRNA/TCR-seq]

Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small animal models. Here we demonstrate that IL-15 is a critical CTCL growth and survival factor. Importantly, a genetically engineered immunodeficient mouse model expressing human IL-15 uniquely supported the growth of patient derived Sezary cells relative to conventional immunodeficient mouse strains. Patient derived xenograft (PDX) SS models recapacitated the pathologic features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single cell transcriptome analysis revealed tissue specific regulation of gene expression and distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of the humanized IL-15, immunodeficient mice for SS PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact. Overall design: Data inludes 1 primary Sezary syndrome patient PBMC, 1 healthy donor PBMC. Samples were enriched for CD4+ cells and subjected to single cell RNA-seq. ***Submitters declare that the raw data will not be deposited in a repository due to their data privacy policy****

塞扎里综合征（Sezary syndrome, SS）是一种罕见且具有侵袭性的皮肤T细胞淋巴瘤（cutaneous T cell lymphoma, CTCL）白血病亚型，目前尚无成熟治疗方案及合适的小动物模型。本研究证实，白细胞介素15（IL-15）是CTCL关键的生长与存活调控因子。尤为重要的是，相较于传统免疫缺陷小鼠品系，表达人源IL-15的基因工程免疫缺陷小鼠模型可特异性支持患者来源的Sezary细胞增殖。患者来源异种移植（patient derived xenograft, PDX）SS模型可重现人类疾病的病理特征，包括皮肤浸润及白血病细胞向外周扩散，且在连续体内传代过程中仍保持对人源IL-15的依赖性。通过单细胞转录组分析对移植细胞进行详细分子表征，结果揭示了基因表达的组织特异性调控模式以及独特的克隆移植特征。综上，本研究证实Sezary细胞的存活与增殖依赖于IL-15信号通路，同时验证了表达人源IL-15的免疫缺陷小鼠可用于构建SS PDX模型。此外，本研究强调需对构建得到的PDX模型开展全面的分子解析，以最大化其转化研究价值。

实验整体设计：本数据集包含1例原发性Sezary综合征患者的外周血单个核细胞（peripheral blood mononuclear cell, PBMC）及1例健康供者的外周血单个核细胞。对样本进行CD4+ T细胞富集后，开展单细胞RNA测序。

***提交者声明：因数据隐私政策，原始数据将不会存入公共数据库***