肿瘤细胞治疗研究
英文原题：Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics.
几乎所有多发性骨髓瘤患者最终都会对治疗失去反应。
几乎所有多发性骨髓瘤患者随时间推移对治疗失去反应。复发/难治性多发性骨髓瘤（RRMM）伴随骨髓瘤细胞的克隆演化，具有异质性基因组畸变和骨髓微环境（BME）的深刻改变。然而，驱动耐药性的分子机制仍不明确。在此，我们通过单细胞 RNA 测序分析了 20 例 RRMM 患者在治疗前/后的异质性肿瘤细胞群体及其与 BME 的复杂相互作用网络。伴有染色体 1q 获得的亚克隆表达特定的转录组特征，并在治疗期间频繁扩增。此外，RRMM 细胞通过上调炎性细胞因子以及与髓系区室的密切相互作用，塑造了一个免疫抑制性 BME。其特征为 PD1+ γδ T 细胞和肿瘤相关巨噬细胞的积累以及造血祖细胞的耗竭。因此，我们的研究解析了 RRMM 中亚克隆的转录特征以及微环境重编程机制，对临床决策具有意义。
Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1 + γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.
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