Department of Pathology, Odense University Hospital, Odense, Denmark.
Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Neuropathol Appl Neurobiol. 2022 Feb;48(2):e12772. doi: 10.1111/nan.12772. Epub 2022 Jan 5.
Glioblastomas are heterogeneous tumours with a rich tumour microenvironment particularly comprised of tumour-associated microglia/macrophages (TAMs), but also containing a population of dedifferentiated/stem-like glioblastoma cells. Both cell populations contribute to tumour aggressiveness and immune evasion through the actions of various signalling molecules. The scavenger and pattern recognition receptor CD204 is associated with a pro-tumourigenic phenotype of TAMs and has a negative prognostic value. Our objective was to investigate the possible interaction between TAMs and dedifferentiated glioblastoma cells and characterise the myeloid phenotype of CD204-enriched glioblastomas.
Double immunohistochemistry and cell counting was performed on eight glioblastoma samples to estimate the expression and interaction level between dedifferentiated/stem-like tumour cells and TAMs. Using the NanoString technology, myeloid transcriptome profiling was performed on 46 glioblastomas, which had been selected based on their protein expression levels of CD204 and ionised calcium-binding adaptor molecule-1 (IBA1). The results were validated by immunohistochemistry and in silico gene expression analyses.
TAMs especially CD204 TAMs accumulated in perivascular and perinecrotic niches in close proximity to podoplanin glioblastoma cells. Gene profiling revealed that CD204-enriched glioblastoma has a unique signature with upregulation of genes related to hypoxia, angiogenesis and invasion, including interleukin-6. The gene signature favoured a poor prognosis in patients with glioblastoma.
This is the first study to characterise the role of CD204 in the myeloid microenvironment of glioblastoma. Our results support the unfavourable prognostic impact of CD204 and suggest that CD204 and interleukin-6 could serve as targets for re-education of TAMs and potentiation of current anti-glioma therapy.
神经胶质瘤是一种具有丰富肿瘤微环境的异质性肿瘤，其中特别包括肿瘤相关的小胶质细胞/巨噬细胞（TAMs），但也含有一群去分化/干细胞样神经胶质瘤细胞。这两种细胞群通过各种信号分子的作用，促进肿瘤侵袭和免疫逃逸。清道夫和模式识别受体 CD204 与 TAMs 的促肿瘤发生表型相关，并且具有负预后价值。我们的目的是研究 TAMs 和去分化神经胶质瘤细胞之间的可能相互作用，并表征富含 CD204 的神经胶质瘤的髓样表型。
对 8 例神经胶质瘤样本进行双重免疫组织化学和细胞计数，以评估去分化/干细胞样肿瘤细胞与 TAMs 之间的表达和相互作用水平。使用 NanoString 技术，对 46 例神经胶质瘤进行髓样转录组谱分析，这些神经胶质瘤是基于其 CD204 和钙结合衔接蛋白分子-1（IBA1）的蛋白表达水平选择的。通过免疫组织化学和计算机基因表达分析验证结果。
TAMs，特别是 CD204 TAMs，在血管周围和坏死周围的龛位中积聚，与 podoplanin 神经胶质瘤细胞相邻。基因谱分析显示，富含 CD204 的神经胶质瘤具有独特的特征，上调与缺氧、血管生成和侵袭相关的基因，包括白细胞介素-6。基因特征对神经胶质瘤患者的预后不利。
这是首次研究 CD204 在神经胶质瘤髓样微环境中的作用。我们的结果支持 CD204 的不利预后影响，并表明 CD204 和白细胞介素-6 可以作为 TAMs 再教育和增强当前抗神经胶质瘤治疗的靶标。
