With tumor genomic and gene-expression profiling (GEP), this study investigated the immune-molecular signatures of a unique cohort of diffuse large B-cell lymphoma of the bone (bone-DLBCL), including primary bone (PB-DLBCL, n = 52) and polyostotic-DLBCL (n = 20), in comparison to nodal DLBCLs with germinal center B-cell (GCB) phenotype (nodal-DLBCL-GCB, n = 34). PB-DLBCL and polyostotic-DLBCL shared similar genomic profiles and transcriptomic signatures, justifying their collective analysis as bone-DLBCL. Differential incidences of EZH2, HIST1H1E, and MYC aberrations (p < 0.05) confirmed the distinct oncogenic evolution between bone-DLBCL and nodal-DLBCL-GCB. Differentially expressed genes were identified between bone-DLBCL and nodal-DLBCL-GCB (p < 0.001), substantiated by distinct gene-set enrichment analysis (GSEA). In contrast to a more ‘depleted’ phenotype for nodal-DLBCL-GCB, bone-DLBCL primarily exhibited an ‘intermediate/rich’ tumor microenvironment (TME) signature (p = 0.001), as determined by a previously published gene set. Unsupervised clustering defined two distinct groups that aligned with previously reported immune-enriched TME clusters: an ‘immune-rich’ cluster largely consisting of bone-DLBCLs (75%, p = 0.002) with superior survival (p = 0.030), and a poor-prognostic ‘immune-low’ cluster, including mostly nodal-DLBCL-GCB (61%). Single-sample (ss)GSEA showed higher scores for regulatory T cells, immunosuppressive/prolymphoma cytokines, and vascular endothelial cells in immune-rich samples (p < 0.001). Additionally, CIBERSORTx revealed a higher abundance of regulatory T cells and activated mast cells in the immune-rich cluster (p < 0.001). These findings were confirmed at protein level, where CD3 and FOXP3 immunochemistry showed significant overlap with the gene-expression data (p < 0.001). Conclusively, PB-DLBCL and polyostotic-DLBCL share immune-molecular TME characteristics, supporting their classification as a unified bone-DLBCL entity. The distinct immune-rich TME profile of bone-DLBCL associated with superior survival potentially shapes emerging immunomodulatory strategies
本研究通过肿瘤基因组与基因表达谱分析，探讨了独特骨弥漫性大B细胞淋巴瘤（bone-DLBCL）队列的免疫分子特征，包括原发性骨DLBCL（PB-DLBCL, n=52）和多灶性骨DLBCL（n=20），并与生发中心B细胞表型的结内DLBCL（nodal-DLBCL-GCB, n=34）进行比较。PB-DLBCL与多灶性骨DLBCL具有相似的基因组图谱和转录组特征，支持将其合并为骨DLBCL进行整体分析。EZH2、HIST1H1E和MYC基因异常的发生率差异（p<0.05）证实了骨DLBCL与结内DLBCL-GCB之间存在不同的致癌演化路径。研究识别出骨DLBCL与结内DLBCL-GCB之间的差异表达基因（p<0.001），并通过差异基因集富集分析（GSEA）得到验证。基于已发表的基因集分析发现，与结内DLBCL-GCB更趋向"免疫耗竭"表型不同，骨DLBCL主要呈现"中等/富集"型肿瘤微环境（TME）特征（p=0.001）。无监督聚类分析定义出两个与既往报道相符的免疫富集TME亚群：主要由骨DLBCL构成的"免疫富集"簇（75%, p=0.002）具有更优生存期（p=0.030），以及预后较差的"免疫低下"簇，其中主要为结内DLBCL-GCB（61%）。单样本GSEA显示免疫富集样本中调节性T细胞、免疫抑制/促淋巴瘤细胞因子及血管内皮细胞的评分更高（p<0.001）。此外，CIBERSORTx分析揭示免疫富集簇中调节性T细胞和活化肥大细胞的丰度更高（p<0.001）。这些发现在蛋白水平得到证实，CD3与FOXP3免疫组化结果与基因表达数据显著吻合（p<0.001）。综上，PB-DLBCL与多灶性骨DLBCL具有共同的免疫分子TME特征，支持将其归类为统一的骨DLBCL实体。骨DLBCL特有的免疫富集型TME特征与更优生存期相关，可能为新兴免疫调节策略提供重要依据。
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