Protein expression from paired biopsies from a patient with METex14 skiping non-small cell lung cancer before and after treatment with neoadjuvant tepotinib (42 days). Protein expression from paired biopsies from a patient with METex14 skiping non-small cell lung cancer before and after treatment with neoadjuvant tepotinib (42 days)

Background: MET inhibitors have demonstrated efficacy in treating patients with non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Advancements in spatial profiling technologies have unveiled the complex dynamics of the tumor microenvironment, a crucial factor in cancer progression and therapeutic response. Using spatial profiling, this study investigates the effects of the MET inhibitor tepotinib on the TME in a case of locally advanced NSCLC with a METex14 skipping alteration. Methods: A patient with resectable stage IIIB NSCLC, unresponsive to neoadjuvant platinum-based doublet chemotherapy, received tepotinib following detection of a METex14 skipping alteration. Paired pre- and post-treatment biopsies were subjected to GeoMx Digital Spatial Profiling using the Cancer Transcriptome Atlas and immune-related protein panels to evaluate shifts in the tumor immune microenvironment (TIME). Results: Tepotinib administration resulted in pathological downstaging to stage IA1, which allowed for a successful lobectomy and evidenced a significant pathological response. The TIME was transformed from an immunosuppressive to a more permissive state, with upregulation of antigen-presenting and pro-inflammatory immune cells. Moreover, a marked decrease in immune checkpoint molecules, including PD-L1, was noted. Spatial profiling identified discrete immune-enriched clusters, indicating the role of tepotinib in modulating immune cell trafficking and function. Conclusions: Tepotinib appears to remodel the TIME in a patient with METex14 skipping NSCLC, possibly increasing responsiveness to immunotherapy. This case supports the integration of genetic profiling into the management of early and locally advanced NSCLC to guide personalized, targeted interventions. These findings highlight the need to further evaluate combinations of MET inhibitors and immunotherapies. Overall design: On the GeoMx Digital Spatial Profiler, regions of interest of 250 micrometers in diameter were selected in the pre-treatment biopsy (15) and tepotinib-treated surgical resection (79) from the same patient, following barcoded antibody incubation (Immune Cell Profiling, Immune Cell Typing, Immune Activation Status, IO Drug Target & PI3K/AKT Signaling panels) and morphology marker staining using SYTO13, TTF1, CD3 and CD33.

研究背景：MET抑制剂（MET inhibitor）已被证实可用于治疗携带METex14跳跃突变（METex14 skipping alterations）的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者。空间 profiling 技术（spatial profiling technologies）的进步揭示了肿瘤微环境（tumor microenvironment, TME）的复杂动态变化，而后者是影响癌症进展与治疗应答的关键因素。本研究借助空间 profiling 技术，针对1例携带METex14跳跃突变的局部晚期NSCLC患者，探讨了MET抑制剂特泊替尼（tepotinib）对其TME的调控作用。
研究方法：1例可切除IIIB期NSCLC患者，经新辅助铂类双药化疗后未获应答，在检测出METex14跳跃突变后接受特泊替尼治疗。收集该患者配对的治疗前后活检标本，采用GeoMx数字空间分析技术（GeoMx Digital Spatial Profiling），结合癌症转录组图谱与免疫相关蛋白组，对肿瘤免疫微环境（tumor immune microenvironment, TIME）的变化进行评估。
研究结果：特泊替尼治疗使患者病理分期降至IA1期，成功实现肺叶切除术，且证实存在显著病理应答。肿瘤免疫微环境从免疫抑制型转变为更具免疫许可性的状态，抗原呈递细胞与促炎免疫细胞表达上调；同时，包括PD-L1在内的免疫检查点分子表达显著下调。空间 profiling 分析鉴定出离散的免疫富集簇，提示特泊替尼可调控免疫细胞的趋化与功能。
研究结论：特泊替尼可重塑携带METex14跳跃突变的NSCLC患者的肿瘤免疫微环境，或可提升其对免疫治疗的应答性。本案例支持将基因 profiling 整合至早期及局部晚期NSCLC的诊疗流程中，以指导个性化靶向干预。本研究结果强调了进一步评估MET抑制剂与免疫治疗联合方案的必要性。
整体实验设计：在GeoMx数字空间分析平台（GeoMx Digital Spatial Profiler）上，对同一患者的治疗前活检标本（选取15个直径250微米的感兴趣区域）与特泊替尼治疗后的手术切除标本（选取79个直径250微米的感兴趣区域）进行分析。实验流程包括条形码标记抗体孵育（涵盖免疫细胞 profiling、免疫细胞分型、免疫激活状态、免疫治疗药物靶点及PI3K/AKT信号通路组），以及使用SYTO13、TTF1、CD3与CD33进行形态学标志物染色。