肿瘤细胞治疗研究
英文原题：Differential FGFR1 copy number status displays unique tumour immune microenvironment in triple-negative breast cancer.
对88份样本进行了下一代测序（NGS），以探索生物学差异。
成纤维细胞生长因子受体1（FGFR1）扩增是一种具有预后和治疗相关性的重要癌症改变，但目前缺乏标准化定义。FGFR1拷贝数（CN）变异与肿瘤微环境（TME）特征之间的关系也仍知之甚少。本研究定义了三阴性乳腺癌（TNBC）中FGFR1扩增，并探讨了不同FGFR1 CN亚型的TME特征，以指导精准治疗。我们分析了182例TNBC肿瘤标本。采用荧光原位杂交（FISH）评估FGFR1 CN状态。对88例样本进行下一代测序（NGS）以探索生物学差异。分析了CD3、CD4和CD8的免疫组织化学（IHC）结果以及临床数据。根据FGFR1/CEN8比值和每细胞平均FGFR1信号数，将样本分为四组。第1组（比值 ≥ 2.0，信号 ≥ 4.0）和第2组（比值 ≥ 2.0，信号 < 4.0）表现出强烈的肿瘤增殖、FGFR信号增强和免疫抑制性TME。相反，第4组（比值 < 2.0，信号 < 4.0）显示出显著增强的免疫细胞浸润（如CD8 + T细胞、NK细胞），并伴有CD3 + /CD8 + T细胞密度升高。第3组（比值 < 2.0，信号 ≥ 4.0）具有异质性：FGFR1 CN ≥ 5的肿瘤类似于第1/2组，而CN < 5的肿瘤则与第4组相似。因此，FGFR1扩增（FGFR1-Amp）被定义为FGFR1/CEN8比值 ≥ 2.0或CN ≥ 5.0（患病率14.29%，26/182）。其余病例为FGFR1中性（FGFR1-Neu）。免疫谱分析显示，与其他亚组相比，FGFR1-Amp & HER2-low TNBC的免疫细胞浸润减少，但致癌信号增强（包括上皮-间质转化、血管生成）。相比之下，FGFR1-Neu肿瘤，尤其是HER2-zero，显示出免疫细胞浸润增加（NK细胞、效应细胞）、MHC I/II分子、活化标志物以及免疫检查点表达升高（如PD-L1、CTLA4、LAG3）。本研究定义了TNBC中的FGFR1扩增并描述了其TME特征。HER2-low TNBC中的FGFR1-Amp与免疫抑制环境相关，可能阻碍HER2-ADC疗效，并提示联合FGFR抑制。相反，具有免疫激活的FGFR1-Neu & HER2-zero肿瘤可能对免疫治疗反应更好。© 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Fibroblast growth factor receptor 1 (FGFR1) amplification, a significant cancer alteration with both prognostic and therapeutic relevance, lacks a standardized definition. The relationship between FGFR1 copy number (CN) variations and tumour microenvironment (TME) characteristics also remains poorly understood. This study defined FGFR1 amplification and investigated TME features across FGFR1 CN subtypes in triple-negative breast cancer (TNBC) to guide precise treatment. We analysed 182 TNBC tumour specimens. FGFR1 CN status was assessed using fluorescence in situ hybridization (FISH). Next-generation sequencing (NGS) was performed on 88 samples to explore biological differences. Immunohistochemical (IHC) results for CD3, CD4, and CD8 along with clinical data were analysed. Samples were categorized into four groups based on the FGFR1/CEN8 ratio and the mean FGFR1 signals per cell. Groups 1 (ratio ≥ 2.0, signals ≥ 4.0) and 2 (ratio ≥ 2.0, signals < 4.0) exhibited robust tumour proliferation, increased FGFR signalling, and an immunosuppressive TME. Conversely, group 4 (ratio < 2.0, signals < 4.0) showed significantly enhanced immune cell infiltration (e.g. CD8 + T cells, NK cells), supported by elevated CD3 + /CD8 + T-cell densities. Group 3 (ratio < 2.0, signals ≥ 4.0) was heterogeneous: tumours with FGFR1 CN ≥ 5 resembled groups 1/2, while those with CN < 5 mirrored group 4. Thus, FGFR1 amplification (FGFR1-Amp) was defined as FGFR1/CEN8 ratio ≥ 2.0 or CN ≥ 5.0 (14.29% prevalence, 26/182). Remaining cases were FGFR1-neutral (FGFR1-Neu). Immune profiling revealed that FGFR1-Amp & HER2-low TNBC had reduced immune cell infiltration but heightened oncogenic signalling (including epithelial-mesenchymal transition, angiogenesis) compared with other subgroups. In contrast, FGFR1-Neu tumours, especially HER2-zero, displayed increased immune cell infiltration (NK cells, effector cells), MHC I/II molecules, activation markers, and elevated immune checkpoint expression (e.g. PD-L1, CTLA4, LAG3). This study defines FGFR1 amplification in TNBC and characterizes its TME. FGFR1-Amp in HER2-low TNBC correlates with an immunosuppressive environment, potentially hindering HER2-ADC efficacy and suggesting combined FGFR inhibition. Conversely, FGFR1-Neu & HER2-zero tumours with immune activation may respond better to immunotherapy. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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