Artzi Sara Blaabjerg, Klausen Marc Nihøj, Harwood Dylan Scott Lykke, Michaelsen Signe Regner, Maarup Simone Bendix, Locallo Alessio, Fougner Vincent, Bager Nicolai Schou, Hammouda Nadine Margaretha, Nørøxe Dorte Schou, Hasselbalch Benedikte, Lassen Ulrik, Weischenfeldt Joachim, Kristensen Bjarne Winther
Department of Clinical Medicine and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Department of Pathology, Rigshospitalet, The Bartholin Institute, Copenhagen University Hospital, Copenhagen, Denmark.
Acta Neuropathol. 2025 Sep 17;150(1):29. doi: 10.1007/s00401-025-02937-9.
Immune checkpoint inhibitors have transformed treatment for several cancers, yet clinical trials of programmed cell death protein 1 (PD-1) blockade in glioblastoma (GBM) have consistently failed to show therapeutic benefit. While some studies have reported treatment-related transcriptional changes, particularly in T cells, findings remain limited and inconsistent. The aim of this study was to investigate changes in tumor cells and tumor-associated macrophages (TAMs) after PD-1 blockade in recurrent GBM using spatial transcriptomics. We performed Digital Spatial Profiling (GeoMx, NanoString) on FFPE tumor samples from 26 patients with matched primary and recurrent IDH-wildtype GBM, including 16 patients who received neoadjuvant nivolumab at recurrence. Tumor (SOX2⁺) and TAM (IBA1⁺) segments were selected for targeted spatial analysis. Following quality control and filtering, transcriptomic profiles were compared between nivolumab-treated and untreated recurrent tumors. PD-1 blockade did not induce detectable gene expression changes in either tumor cells or TAMs. There were no significant differences in global expression profiles or in more targeted analyses of malignant cell states, cell cycle activity, interferon signaling, or myeloid transcriptional programs. These results consistently indicate that neoadjuvant PD-1 blockade does not elicit measurable responses at the spatial transcriptomic level in tumor cells or TAMs in recurrent GBM. These findings align with the lack of clinical benefit observed in trials and highlight the need for alternative strategies to improve immunotherapy outcomes in GBM.
免疫检查点抑制剂已经改变了多种癌症的治疗方式，然而，针对胶质母细胞瘤（GBM）的程序性细胞死亡蛋白1（PD-1）阻断临床试验一直未能显示出治疗益处。虽然一些研究报告了与治疗相关的转录变化，特别是在T细胞中，但研究结果仍然有限且不一致。本研究的目的是使用空间转录组学研究复发性GBM中PD-1阻断后肿瘤细胞和肿瘤相关巨噬细胞（TAM）的变化。我们对26例原发性和复发性异柠檬酸脱氢酶野生型GBM匹配患者的福尔马林固定石蜡包埋（FFPE）肿瘤样本进行了数字空间分析（GeoMx，NanoString），其中包括16例复发时接受新辅助纳武单抗治疗的患者。选择肿瘤（SOX2⁺）和TAM（IBA1⁺）区域进行靶向空间分析。经过质量控制和过滤后，比较了纳武单抗治疗和未治疗的复发性肿瘤之间的转录组谱。PD-1阻断在肿瘤细胞或TAM中均未诱导可检测到的基因表达变化。在整体表达谱或对恶性细胞状态、细胞周期活性、干扰素信号或髓系转录程序的更有针对性分析中，均无显著差异。这些结果一致表明，新辅助PD-1阻断在复发性GBM的肿瘤细胞或TAM的空间转录组水平上不会引发可测量的反应。这些发现与试验中观察到的缺乏临床益处一致，并强调需要采用替代策略来改善GBM的免疫治疗结果。
