Xue Qianqian, Wang Yue, Zheng Qiang, Huang Ziling, Lin Yicong, Jin Yan, Li Yuan
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Curr Oncol. 2025 Jul 14;32(7):403. doi: 10.3390/curroncol32070403.
MET exon 14 skipping mutations have emerged as significant driver alterations in non-small-cell lung cancer (NSCLC), contributing to tumor progression. This study examines the immune microenvironment in NSCLC patients with these mutations and its prognostic implications. We performed multiplex immunofluorescence (mIF) staining on formalin-fixed paraffin-embedded (FFPE) tissue samples from nine NSCLC patients, including four recurrent/metastatic and five non-recurrent/non-metastatic patients. Two panels assessed immune cell markers (CD8, CD4, CD20, CD68, and FoxP3) and immune checkpoints (PD-L1, LAG3, and TIM3). Immune cell infiltration and checkpoint expression were analyzed using HALO software (version 3.6.4134.464). Nearest neighbor analysis was conducted to assess the proximity of immune cells to tumor cells. Univariate Cox regression analysis assessed factors associated with disease-free survival (DFS). CD8+TIM3+ and CD8+LAG3+ cells were predominantly located in the tumor parenchyma of recurrent/metastatic patients but localized to the stroma in non-recurrent/non-metastatic patients. Non-recurrent/non-metastatic patients exhibited a higher density of tertiary lymphoid structures and closer proximity of CD20+ B cells, CD8+TIM3+, and CD8+LAG3+ cells to tumor cells compared to recurrent/metastatic patients, though the differences were not statistically significant. Cox regression analysis suggested a potential association between higher densities of CD8+TIM3+ cells and improved DFS (HR = 0.89), though these findings did not reach statistical significance. Our findings suggest that differences in immune microenvironmental factors, particularly those related to immune checkpoint expression (TIM3 and LAG3), may influence clinical outcomes in NSCLC patients with MET exon 14 skipping mutations. Further studies are needed to validate these observations and explore potential therapeutic implications.
MET外显子14跳跃突变已成为非小细胞肺癌（NSCLC）中重要的驱动性改变，促进肿瘤进展。本研究检测了具有这些突变的NSCLC患者的免疫微环境及其预后意义。我们对9例NSCLC患者的福尔马林固定石蜡包埋（FFPE）组织样本进行了多重免疫荧光（mIF）染色，其中包括4例复发/转移患者和5例非复发/非转移患者。两组检测免疫细胞标志物（CD8、CD4、CD20、CD68和FoxP3）和免疫检查点（PD-L1、LAG3和TIM3）。使用HALO软件（3.6.4134.464版）分析免疫细胞浸润和检查点表达。进行最近邻分析以评估免疫细胞与肿瘤细胞的接近程度。单因素Cox回归分析评估与无病生存期（DFS）相关的因素。CD8+TIM3+和CD8+LAG3+细胞主要位于复发/转移患者的肿瘤实质中，但在非复发/非转移患者中定位于基质。与复发/转移患者相比，非复发/非转移患者的三级淋巴结构密度更高，CD20+B细胞、CD8+TIM3+和CD8+LAG3+细胞与肿瘤细胞的距离更近，尽管差异无统计学意义。Cox回归分析表明，CD8+TIM3+细胞密度较高与DFS改善之间可能存在关联（HR = 0.89），尽管这些发现未达到统计学意义。我们的研究结果表明，免疫微环境因素的差异，特别是与免疫检查点表达（TIM3和LAG3）相关的因素，可能影响具有MET外显子14跳跃突变的NSCLC患者的临床结局。需要进一步研究来验证这些观察结果并探索潜在的治疗意义。
