Enemark Marie Hairing, Jensen Maja Lund, Andersen Maja Dam, Plesner Trine Lindhardt, Hamilton-Dutoit Stephen, Ludvigsen Maja
Department of Hematology, Aarhus University Hospital, 8200 Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
Cancers (Basel). 2024 Oct 21;16(20):3553. doi: 10.3390/cancers16203553.
Follicular lymphoma (FL) presents significant clinical heterogeneity, with some patients experiencing transformation into an aggressive disease, a key contributor to FL-related mortality. Based on gene expression profiles, this study aimed to provide insights into immunological differences associated with transformation. Gene expression analysis using the NanoString nCounter Tumor Signaling 360 Panel was performed on diagnostic lymphoma samples from 70 FL patients diagnosed in the rituximab era, either non-transforming FL (nt-FL, n = 34) or subsequently transforming FL (st-FL, n = 36), with paired high-grade transformed FL (tFL, n = 36) samples available. In silico immunophenotyping was performed to infer immune cell infiltration using the CIBERSORTx algorithm. The gene expression analysis revealed 164 significantly differentially expressed genes, distinguishing st-FL from nt-FL and generally presenting an upregulation of B cell-related genes (CD40, IRF4, RELB), immunosuppressive molecules (IL10, SOCS3), and immune checkpoint molecules (CD276, TIM3). Analysis of immune cell proportions indicated significant differences in infiltrates of M1-like macrophages ( = 0.007) and neutrophils ( = 0.012) in nt-FL versus st-FL samples. Transformation-free survival (TFS) was associated with high numbers of both these cellular subsets ( = 0.006 and 0 = 0.002, respectively). This was even more evident when combined with inferior TFS in lymphomas with high infiltrates of both cell types ( < 0.001). After transformation, tFL samples showed a reduction in T follicular helper cells ( = 0.008) and an increase in immunosuppressive M2-like macrophages and neutrophils ( < 0.001 and = 0.028, respectively). By elucidating the distinct molecular and immune landscapes of FL at the time of diagnosis and transformation, this study underscores the importance of immune microenvironment in FL transformation and patient outcome.
滤泡性淋巴瘤（FL）呈现出显著的临床异质性，一些患者会转化为侵袭性疾病，这是FL相关死亡率的一个关键因素。基于基因表达谱，本研究旨在深入了解与转化相关的免疫差异。使用NanoString nCounter肿瘤信号360面板对70例在利妥昔单抗时代确诊的FL患者的诊断性淋巴瘤样本进行基因表达分析，这些患者分为非转化性FL（nt-FL，n = 34）或随后转化的FL（st-FL，n = 36），并提供了配对的高级别转化FL（tFL，n = 36）样本。使用CIBERSORTx算法进行计算机免疫表型分析以推断免疫细胞浸润情况。基因表达分析揭示了164个显著差异表达的基因，这些基因区分了st-FL和nt-FL，并且通常呈现B细胞相关基因（CD40、IRF4、RELB）、免疫抑制分子（IL10、SOCS3）和免疫检查点分子（CD276、TIM3）的上调。免疫细胞比例分析表明，nt-FL与st-FL样本中M1样巨噬细胞（P = 0.007）和中性粒细胞（P = 0.012）的浸润存在显著差异。无转化生存期（TFS）与这两种细胞亚群的高数量相关（分别为P = 0.006和P = 0.002）。当与两种细胞类型浸润高的淋巴瘤中较差的TFS相结合时，这种情况更加明显（P < 0.001）。转化后，tFL样本显示T滤泡辅助细胞减少（P = 0.008），免疫抑制性M2样巨噬细胞和中性粒细胞增加（分别为P < 0.001和P = 0.028）。通过阐明FL在诊断和转化时独特的分子和免疫格局，本研究强调了免疫微环境在FL转化和患者预后中的重要性。
