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-DR^lowCD11b⁺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.

骨髓 （BM） 微环境在调节华氏巨球蛋白血症 （WM） 抗肿瘤免疫反应中的作用仍然知之甚少。在这里，我们对来自 WM 患者的非恶性 （CD19-CD138^-） BM 细胞进行了转录和表型分析，重点关注髓源性抑制细胞 （MDSC），以更深入地了解它们在 WM 中的作用。我们发现，与正常对照相比，WM 患者的 HLA-DR^低CD11b ⁺ CD33 ⁺ MDSCs 显著增加，主要是多形核 （PMN）-MDSCs 的扩展。WM MDSCs 的单细胞免疫基因组学分析确定了免疫抑制基因特征，与干扰素和肿瘤坏死因子 （TNF） 信号相关的炎症通路上调。与炎症和免疫抑制环境相关的基因特征主要在 PMN-MDSC 中表达。在体外，WM PMN-MDSCs 表现出强大的 T 细胞抑制，粒细胞集落刺激因子 （G-CSF） 和 TNFα 显著增强了它们的活力和扩增。此外，BM 恶性 B 细胞比单核细胞 MDSC 更能吸引 PMN-MDSC。总的来说，这些数据表明，恶性 WM B 细胞主动募集 PMN-MDSC，通过直接 T 细胞抑制促进免疫抑制性 BM 微环境，而微环境中 G-CSF/TNFα 的释放进一步促进 PMN-MDSC 扩增，进而免疫抑制。因此，靶向 PMN-MDSC 可能代表了 WM 患者的潜在治疗策略。