骨髓免疫生态系统在浆细胞骨髓瘤中形成达拉单抗获得性耐药

IF 13.4 1区 医学 Q1 HEMATOLOGY
Yun Wang, Shuzhao Chen, Zhijian Liang, Robert Peter Gale, Shutong Liu, Xiaoqin Chen, Peidong Chi, Yiling Song, Yingchun Zhang, Weida Wang, Juan Li, Zhongjun Xia, Yang Liang, Xiaojun Huang
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引用次数: 0

摘要

Daratumumab是一种抗cd38单克隆抗体,是治疗浆细胞骨髓瘤(PCM)的有效药物。然而,许多最初的应答者复发。我们比较了来自治疗前受试者的配对样本,然后获得了对daratumumab的耐药性。我们首先使用单细胞RNA测序和数字空间分析器(DSP)。与治疗前样品相比,具有衰竭表型和IFN-γ特征的细胞毒性cd8阳性t细胞的比例增加,而nk细胞的比例减少并具有增加的抑制性表型。肿瘤浆细胞中CD38的转录减少。由DSP定义的肿瘤中心免疫细胞数量显著减少,同时衰竭特征增加。在4个外部队列(GSE24080、GSE136337、GSE57317和coMMpass)中,获得性耐药特征和升高的PCM亚群表型与较差的预后相关。通过单细胞调控网络推断,我们将获得性耐药中的前20个上调调控与上调基因交叉,确定MYC调控是肿瘤浆细胞获得性耐药的关键激活因子。此外,体外和体内实验数据表明,骨髓免疫生态系统细胞分泌的IFN-γ激活MYC,这与获得性达拉单抗耐药相关。我们的数据为获得性daratumumab耐药提供了见解,并提出了潜在的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The bone marrow immune ecosystem shapes daratumumab acquired resistance in plasma cell myeloma

The bone marrow immune ecosystem shapes daratumumab acquired resistance in plasma cell myeloma

The bone marrow immune ecosystem shapes daratumumab acquired resistance in plasma cell myeloma
Daratumumab, an anti-CD38 monoclonal antibody, is an effective therapy for plasma cell myeloma (PCM). However, many initial responders relapse. We compared paired samples from subjects pre-therapy and then acquired resistance to daratumumab. We first used single-cell RNA sequencing and digital spatial profiler (DSP). The proportion of cytotoxic CD8-positive T-cells with an exhaustion phenotype and an IFN-γ signature increased in resistance compared with pre-therapy samples, whilst the proportion of NK-cells decreased and had an increased inhibitory phenotype. Transcription of CD38 in neoplastic plasma cells decreased. Numbers of immune cells in cancer centre defined by DSP were significantly decreased in parallel with an increased exhaustion signature. The acquired resistance signature and elevated PCM subset phenotype were associated with worse prognosis in 4 external cohorts (GSE24080, GSE136337, GSE57317, and coMMpass). Using single-cell regulatory network inference, we identified MYC regulation as a key activated factor for acquired resistance in neoplastic plasma cells by intersecting the top 20 upregulated regulons and upregulated genes in acquired resistance. Furthermore, data from in vitro and in vivo experiments indicate that IFN-γ secreted by cells of bone marrow immune ecosystem activates MYC, which correlates with acquired daratumumab resistance. Our data provide insights into acquired daratumumab resistance and suggest potential therapeutic strategies.
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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