文章：

华氏巨球蛋白血症中扩增的肿瘤相关多形核髓源性抑制细胞表现出免疫抑制活性

Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity

原文发布日期：2024-12-18

DOI: 10.1038/s41408-024-01173-w

类型: Article

开放获取: 是

英文摘要：

The role of the bone marrow (BM) microenvironment in regulating the antitumor immune response in Waldenstrom macroglobulinemia (WM) remains poorly understood. Here we transcriptionally and phenotypically profiled non-malignant (CD19- CD138-) BM cells from WM patients with a focus on myeloid derived suppressive cells (MDSCs) to provide a deeper understanding of their role in WM. We found that HLA-DRlowCD11b+CD33+ MDSCs were significantly increased in WM patients as compared to normal controls, with an expansion of predominantly polymorphonuclear (PMN)-MDSCs. Single-cell immunogenomic profiling of WM MDSCs identified an immune-suppressive gene signature with upregulated inflammatory pathways associated with interferon and tumor necrosis factor (TNF) signaling. Gene signatures associated with an inflammatory and immune suppressive environment were predominately expressed in PMN-MDSCs. In vitro, WM PMN-MDSCs demonstrated robust T-cell suppression and their viability and expansion was notably enhanced by granulocyte colony stimulating factor (G-CSF) and TNFα. Furthermore, BM malignant B-cells attracted PMN-MDSCs to a greater degree than monocytic MDSCs. Collectively, these data suggest that malignant WM B cells actively recruit PMN-MDSCs which promote an immunosuppressive BM microenvironment through a direct T cell inhibition, while release of G-CSF/TNFα in the microenvironment further promotes PMN-MDSC expansion and in turn immune suppression. Targeting PMN-MDSCs may therefore represent a potential therapeutic strategy in patients with WM.
 

摘要翻译： 

骨髓微环境在华氏巨球蛋白血症（WM）抗肿瘤免疫反应中的调控作用尚未明确。本研究通过对WM患者的非恶性（CD19- CD138-）骨髓细胞进行转录组和表型分析，重点关注髓源性抑制细胞（MDSCs），以深入探讨其在WM中的作用。研究发现，与正常对照组相比，WM患者中HLA-DRlowCD11b+CD33+ MDSCs显著增加，其中以多形核髓源性抑制细胞（PMN-MDSCs）扩增为主。通过单细胞免疫基因组分析，发现WM MDSCs具有免疫抑制性基因特征，且与干扰素和肿瘤坏死因子（TNF）信号传导相关的炎症通路上调。与炎症及免疫抑制环境相关的基因特征主要在PMN-MDSCs中表达。在体外实验中，WM PMN-MDSCs表现出强烈的T细胞抑制功能，且其存活与扩增能力在粒细胞集落刺激因子（G-CSF）和TNFα作用下显著增强。此外，与单核细胞源性MDSCs相比，WM恶性B细胞对PMN-MDSCs的趋化作用更为显著。综合而言，这些数据表明WM恶性B细胞主动招募PMN-MDSCs，通过直接抑制T细胞促进免疫抑制性骨髓微环境的形成，而微环境中G-CSF/TNFα的释放进一步推动PMN-MDSCs扩增，进而加剧免疫抑制。因此，靶向PMN-MDSCs可能成为WM患者的潜在治疗策略。

原文链接：

Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity