van Hijfte Levi, Geurts Marjolein, de Heer Iris, Ghisai Santoesha A, Balcioglu Hayri E, Hoogstrate Youri, Vallentgoed Wies R, Head Rania, Luning Rosa, van den Bosch Thierry, Westerman Bart, Wesseling Pieter, Joyce Johanna A, French Pim, Debets Reno
Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Department of Medical Oncology, Laboratory of Tumor Immunology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Nat Commun. 2025 Jan 29;16(1):1156. doi: 10.1038/s41467-025-56441-5.
Isocitrate dehydrogenase 1/2 mutant (IDHmt) astrocytoma is considered a T cell-deprived tumor, yet little is known regarding the phenotypes underlying T cell exclusion. Using bulk, single nucleus and spatial RNA and protein profiling, we demonstrate that a distinct spatial organization underlies T cell confinement to the perivascular space (T cell cuff) in IDHmt astrocytoma. T cell cuffs are uniquely characterized by a high abundance of gemistocytic tumor cells (GTC) in the surrounding stroma. Integrative analysis shows that GTC-high tumors are enriched for lymphocytes and tumor associated macrophages (TAM) and express immune cell migration and activation programs. Specifically, GTCs constitute a distinct sub-cluster of the astrocyte-like tumor cell state that co-localizes with immune reactive TAMs. Neighboring GTCs and TAMs express receptor-ligand pairs characteristic of reactive astrogliosis and glial scarring, such as SPP1/CD44 and IL-1β/IL1R1. Collectively, we reveal that T cell confinement in IDHmt astrocytomas associates with GTC-TAM networks that mimic glial scarring mechanisms.
异柠檬酸脱氢酶1/2突变型（IDHmt）星形细胞瘤被认为是一种缺乏T细胞的肿瘤，但对于T细胞排斥背后的表型知之甚少。通过批量、单核以及空间RNA和蛋白质分析，我们证明了一种独特的空间组织是IDHmt星形细胞瘤中T细胞局限于血管周围空间（T细胞套）的基础。T细胞套的独特特征是周围基质中富含肥胖型星形细胞瘤细胞（GTC）。综合分析表明，高GTC肿瘤富含淋巴细胞和肿瘤相关巨噬细胞（TAM），并表达免疫细胞迁移和激活程序。具体而言，GTC构成了星形胶质细胞样肿瘤细胞状态的一个独特亚群，与免疫反应性TAM共定位。相邻的GTC和TAM表达反应性星形胶质细胞增生和胶质瘢痕形成的特征性受体-配体对，如SPP1/CD44和IL-1β/IL1R1。总体而言，我们揭示了IDHmt星形细胞瘤中T细胞的局限与模拟胶质瘢痕形成机制的GTC-TAM网络有关。
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