Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating and uniformly lethal pediatric brain tumor disease characterized by aggressive progression and resistance to current therapies. As a critical component of the tumor immune microenvironment (TIME), macrophages, including brain-resident microglia, play a pivotal role in shaping immune responses, while their functional contribution in DIPG remains poorly understood. To characterize the molecular landscape of DIPG, bulk RNA sequencing was performed on tumor and matched normal brain tissues from autopsy samples of DIPG patients. Differential expression analysis revealed significant upregulation of macrophage-recruiting chemokines and macrophage signature genes in tumor samples. Pathway enrichment analysis highlighted the prominent activation of MHC pathways, mostly MHC class II (MHCII) genes and MHCII-related transcription activators and ligands (e.g., CIITA, CD4, and LAG3), notably upregulated in tumor cells, suggesting their potential role in modulating the immune response to tumor cells and shaping the TME. Single-cell RNA sequencing was conducted on 20,839 single cells isolated from autopsy specimens of DIPG patients and 6128 cells from public datasets to further delineate the TME composition. Bioinformatics analysis revealed that microglia and tumor-associated macrophages were the most abundant immune cell populations, although the overall immune cell proportion was significantly lower compared to adult glioblastoma (GBM). The data indicate an immunosuppressive TME in DIPG, driven by macrophage-dominated interactions, particularly through MHCII-mediated pathways. These findings will enhance the understanding of macrophage driven TME in DIPG and will identify the dominant role of macrophages in shaping the immunosuppressive TME. Targeting macrophage-related pathways, particularly those involving MHCII, offers critical insights into the mechanisms by which macrophages respond to tumor cells. Leveraging this understanding and harnessing the functional roles of macrophages holds promise for enhancing immunotherapy and improving outcomes for DIPG patients.
Wang et al. (Fri,) studied this question.