Background: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.Methods: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.Results: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 (p= 0.007) and neutrophils (p= 0.012) in nt-FL versus st-FL samples. Transformation-free survival (TFS) was associated with high numbers of both these cellular subsets (p= 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 (p< 0.001). After transformation, tFL samples showed a reduction in T follicular helper cells (p= 0.008) and an increase in immunosuppressive M2-like macrophages and neutrophils (p< 0.001 andp= 0.028, respectively).Conclusion: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.
背景：滤泡性淋巴瘤（FL）具有显著的临床异质性，部分患者会转化为侵袭性疾病，这是FL相关死亡的关键因素。本研究基于基因表达谱，旨在揭示与转化相关的免疫学差异。 方法：对利妥昔单抗时代诊断的70例FL患者的诊断性淋巴瘤样本进行基因表达分析，使用NanoString nCounter肿瘤信号360 Panel检测。样本包括非转化型FL（nt-FL，n=34）和后续转化型FL（st-FL，n=36），并获取了配对的侵袭性转化型FL（tFL，n=36）样本。通过CIBERSORTx算法进行计算机模拟免疫表型分析，以推断免疫细胞浸润情况。 结果：基因表达分析揭示了164个显著差异表达基因，能够区分st-FL与nt-FL，主要表现为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。免疫细胞比例分析显示，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）。当两种细胞类型均高度浸润的淋巴瘤中TFS较差时，这种关联更为明显（p<0.001）。转化后，tFL样本显示滤泡辅助性T细胞减少（p=0.008），而免疫抑制性M2样巨噬细胞和中性粒细胞增加（分别为p<0.001和p=0.028）。 结论：通过阐明FL在诊断和转化时独特的分子和免疫景观，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。
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