文章：

复发性多发性骨髓瘤表现出独特的免疫微环境模式及恶性细胞介导的免疫抑制

Relapsed multiple myeloma demonstrates distinct patterns of immune microenvironment and malignant cell-mediated immunosuppression

原文发布日期：2021-03-01

DOI: 10.1038/s41408-021-00440-4

类型: Article

开放获取: 是

英文摘要：

Immunotherapy has shown efficacy in relapsed multiple myeloma (MM). However, these therapies may depend on a functional tumor immune microenvironment (iTME) for their efficacy. Characterizing the evolution of the iTME over the disease course is necessary to optimize the timing of immunotherapies. We performed mass cytometry, cytokine analysis, and RNA sequencing on bone marrow samples from 39 (13 newly diagnosed [NDMM], 11 relapsed pre-daratumumab exposure [RMM], and 13 triple-refractory [TRMM]) MM patients. Three distinct cellular iTME clusters were identified; cluster 1 comprised mainly of NDMM and RMM patients; and clusters 2 and 3 comprised primarily of TRMM patients. We showed that naive T cells were decreased in clusters 2 and 3, cluster 2 was characterized by increased senescent T cells, and cluster 3 by decreased early memory T cells. Plasma cells in clusters 2 and 3 upregulated E2F transcription factors and MYC proliferation pathways, and downregulated interferon, TGF-beta, interleuking-6, and TNF-αlpha signaling pathways compared to cluster 1. This study suggests that the MM iTME becomes increasingly dysfunctional with therapy whereas the MM clone may be less dependent on inflammation-mediated growth pathways and less sensitive to IFN-mediated immunosurveillance. Our findings may explain the decreased sensitivity of TRMM patients to novel immunotherapies.
 

摘要翻译： 

免疫治疗在复发多发性骨髓瘤（MM）中显示出疗效。然而，这些疗法的效果可能依赖于功能正常的肿瘤免疫微环境（iTME）。为优化免疫治疗时机，有必要明确iTME在疾病进程中的演变特征。我们对39例MM患者（包括13例新诊断[NDMM]、11例达雷妥尤单抗治疗前复发[RMM]及13例三药难治性[TRMM]）的骨髓样本进行了质谱流式细胞术、细胞因子分析和RNA测序。研究识别出三种不同的细胞性iTME集群：集群1主要由NDMM和RMM患者组成；集群2和3则主要为TRMM患者。研究发现，集群2和3中初始T细胞减少，集群2以衰老T细胞增加为特征，而集群3表现为早期记忆T细胞减少。与集群1相比，集群2和3中的浆细胞上调了E2F转录因子和MYC增殖通路，同时下调了干扰素、TGF-β、白细胞介素-6和TNF-α信号通路。本研究表明，随着治疗进程，MM的iTME功能失调逐渐加剧，而MM克隆可能对炎症介导的生长通路依赖度降低，并对干扰素介导的免疫监视敏感性减弱。这些发现或可解释TRMM患者对新型免疫疗法敏感性下降的现象。

原文链接：

Relapsed multiple myeloma demonstrates distinct patterns of immune microenvironment and malignant cell-mediated immunosuppression