Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. Using CIBERSORT, mass cytometry (CyTOF), and single-cell RNA sequencing (scRNA-Seq), we examined innate and adaptive immune changes across these stages. We found a decrease in granulocytes in the TME predicts MM outcomes. HLA-DR is reduced in CD16+ monocytes and plasmacytoid dendritic cells, while myeloid dendritic cells show decreased expression of stress and immune-response genes. NK cells and CD8+ T cells shift from a GZMK+ to a GZMB+ cytotoxic phenotype in the TME, with increased inhibitory markers TIM3 and TIGIT. In paired samples, the proportion and gene expression pattern in patient-specific GZMB+CD8+ T cells remain largely unchanged despite MM progression. Our findings provide a comprehensive immune landscape of MM and its precursors, offering insights into therapeutic strategies. Enhancing neutrophil and NK cell cytotoxicity, tumor antigen presentation, and CD8+ T cell versatility in precursor stages may prevent MM progression.
肿瘤免疫微环境改变在多发性骨髓瘤发生早期即已出现。本研究旨在系统描绘从癌前阶段（意义未明的单克隆丙种球蛋白病和冒烟型多发性骨髓瘤）到新诊断多发性骨髓瘤的肿瘤免疫微环境及肿瘤-免疫相互作用特征，并与健康供体进行对比。通过CIBERSORT分析、质谱流式细胞术和单细胞RNA测序技术，我们揭示了这些阶段中天然免疫与适应性免疫的动态变化。研究发现肿瘤免疫微环境中粒细胞减少可预测多发性骨髓瘤预后。CD16+单核细胞和浆细胞样树突状细胞中HLA-DR表达下降，而髓样树突状细胞的应激反应及免疫应答相关基因表达降低。NK细胞和CD8+ T细胞在肿瘤免疫微环境中从GZMK+向GZMB+细胞毒性表型转化，抑制性标志物TIM3和TIGIT表达增加。配对样本分析显示，尽管多发性骨髓瘤发生进展，患者特异性GZMB+CD8+ T细胞的比例和基因表达模式基本保持稳定。本研究绘制了多发性骨髓瘤及其癌前阶段的完整免疫图谱，为治疗策略提供了新见解。在癌前阶段增强中性粒细胞与NK细胞毒性、改善肿瘤抗原呈递能力以及提升CD8+ T细胞多功能性，或可阻止多发性骨髓瘤进展。
Multi-omics reveal immune microenvironment alterations in multiple myeloma and its precursor stages
肿瘤(癌症)患者之家