Zahedi Shadi, Riemondy Kent, Liu Tian, Griesinger Andrea M, Donson Andrew M, Apfelbaum April A, Fu Rui, Grandvallet Contreras Julian, Crespo Michele, DeSisto John, Groat Madeline M, Bratbak Emil, Green Adam, Hankinson Todd C, Handler Michael, Vibhakar Rajeev, Willard Nicholas, Foreman Nicholas K, Phang Tzu, Mulcahy Levy Jean
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Pediatrics, Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, Colorado, USA.
Brain Pathol. 2025 Jun 30:e70023. doi: 10.1111/bpa.70023.
Pediatric low-grade gliomas (pLGG) comprise 35% of all brain tumors. Despite favorable survival, patients experience significant morbidity from disease and treatments. A deeper understanding of pLGG biology is essential to identify novel, more effective, and less toxic therapies. We utilized single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and cytokine analyses to characterize and understand tumor and immune cell heterogeneity of pilocytic astrocytoma (PA) and ganglioglioma (GG). scRNA-seq revealed tumor and immune cells within the tumor microenvironment (TME). Tumor cell subsets include both progenitor and mature cell populations. Immune cells included myeloid and lymphocytic cells. There was a significant difference between the prevalence of two major myeloid subclusters between PA and GG. Bulk and single-cell cytokine analyses evaluated the immune cell signaling cascade with distinct immune phenotypes among tumor samples. KIAA1549-BRAF tumors appeared more immunogenic, secreting higher levels of immune cell activators and chemokines, compared to BRAF V600E tumors. Spatial transcriptomics revealed the differential gene expression of these chemokines and their location within the TME. A multi-pronged analysis demonstrated the complexity of the PA and GG TME and differences between genetic drivers that may influence their response to immunotherapy. Further investigation of immune cell infiltration and tumor-immune interactions is warranted.
小儿低级别胶质瘤（pLGG）占所有脑肿瘤的35%。尽管生存率较高，但患者仍会因疾病和治疗而出现明显的发病情况。深入了解pLGG生物学对于确定新的、更有效且毒性更小的治疗方法至关重要。我们利用单细胞RNA测序（scRNA-seq）、空间转录组学和细胞因子分析来表征和理解毛细胞型星形细胞瘤（PA）和神经节胶质瘤（GG）的肿瘤及免疫细胞异质性。scRNA-seq揭示了肿瘤微环境（TME）中的肿瘤细胞和免疫细胞。肿瘤细胞亚群包括祖细胞和成熟细胞群体。免疫细胞包括髓系细胞和淋巴细胞。PA和GG之间两个主要髓系亚群的患病率存在显著差异。大量和单细胞细胞因子分析评估了肿瘤样本中具有不同免疫表型的免疫细胞信号级联反应。与BRAF V600E肿瘤相比，KIAA1549-BRAF肿瘤似乎更具免疫原性，分泌更高水平的免疫细胞激活剂和趋化因子。空间转录组学揭示了这些趋化因子的差异基因表达及其在TME中的位置。多方面分析证明了PA和GG TME的复杂性以及可能影响其对免疫治疗反应的基因驱动因素之间的差异。有必要进一步研究免疫细胞浸润和肿瘤-免疫相互作用。
