HGG-47. SPATIAL SINGLE-CELL PROTEOMIC ANALYSIS MAPS THE DISTINCT PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA TUMOR ENTITIES AND DEFINES THEIR TUMOR AND IMMUNE MICROENVIRONMENTS

Lucia Lisa Petrilli,Giulio Spinozzi, Lucia Di Crocco, Antonio Salanitro,Sabrina Rossi,Dario Bressan, Alfredo Cerimele,Francesca Diomedi-Camassei,Evelina Miele,Antonella Cacchione,Giada Del Baldo,Giovanna Stefania Colafati,Andrea Carai,Franco Locatelli,Angela Mastronuzzi,Maria Vinci

NEURO-ONCOLOGY（2024）

Bambino Gesu Childrens Hosp IRCCS | Univ Cambridge | Bambino Gesù Children's Hospital

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Abstract

Paediatric-type diffuse high-grade gliomas (pDHGG) are a group of molecularly and clinically defined tumor entities of the central nervous system. The investigation of the spatial organization of pDHGG tissues may provide new insights to decipher their heterogeneous nature and identify vulnerabilities in their aggressive behaviour. Here we exploit Imaging Mass Cytometry (IMC), a spatial biology approach enabling multiplex tissue phenotyping at single-cell resolution. We used 16 total formalin-fixed paraffin-embedded (FFPE) tissues from 4 patients including 1 Diffuse hemispheric glioma H3G34-mutant (DHG-H3G34), 1 Diffuse pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (DHGG-WT) and 2 Diffuse midline glioma H3K27-altered (DMG-H3K27, 1 H3.3K27M and 1 H3.1K27M). Classical pathology assessment and DNA methylation profile were also performed. For IMC staining, 2 metal-tag custom-designed antibody panels (tumour and immune) of 31 antibodies were used. The panels include antibodies for differentiated and stem-cell markers, extracellular matrices, immune markers and H3K27M and H3.3G34R variants. An IMC analysis pipeline was developed: images are extracted in tiff format from the proprietary MCD files produced by Hyperion instrument, filtered to remove hot pixels via top-hat and OpenCV in Python, segmented using steinbock and analysed using the IMC Data Analysis toolbox in R, using docker. A total of 209 mm2 of tissue were analysed. IMC analysis showed that DHG-H3G34 displays a higher heterogeneity in terms of cell phenotypes compared to the other tumor entities. Moreover, immune infiltrate of T, B cells, NK and monocytes was observed in the DHG-H3G34 and DHGG-WT tissues, while the DMG-H3K27 had low/no immune infiltrate with the H3.3K27M showing higher PDL-1 expression. Analysis of longitudinal and multi-region samples highlighted trajectories of tumor evolution and identification of extracellular matrix niches in tumor core versus the infiltrative front. Our study provides novel insights into pDHGG complex biology by investigating their tissue architecture, spatial organization and cell-cell interactions.

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【要点】：本研究利用成像质谱流式技术（IMC）分析了儿童弥漫性高级别胶质瘤（pDHGG）的肿瘤和免疫微环境，揭示了其空间组织结构和异质性特征。

【方法】：采用成像质谱流式技术（IMC）进行单细胞分辨率下的多参数组织表型分析。

【实验】：研究使用16份福尔马林固定石蜡包埋（FFPE）组织样本，包括1例弥漫性半球胶质瘤H3G34突变型（DHG-H3G34）、1例弥漫性儿童型高级别胶质瘤H3野生型和IDH野生型（DHGG-WT）以及2例弥漫性中线胶质瘤H3K27改变型（DMG-H3K27），通过IMC分析，发现DHG-H3G34细胞表型异质性较高，且在DHG-H3G34和DHGG-WT组织中观察到T细胞、B细胞、自然杀伤细胞和单核细胞的免疫浸润，而DMG-H3K27免疫浸润较低或无，H3.3K27M显示PDL-1表达较高。

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