Microglia and monocyte-derived macrophages drive progression of pediatric high-grade gliomas and are transcriptionally shaped by histone mutations

Pediatric high-grade gliomas (pHGGs), including hemispheric pHGGs and diffuse midline gliomas (DMGs), harbor mutually exclusive tumor location-specific histone mutations. Using immunocompetent de novo mouse models of pHGGs, we demonstrated that myeloid cells were the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrated the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics were identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrated enrichment of DAMs. Genetic ablation of chemokines Ccl8 and Ccl12 resulted in a reduction of DAMs and an increase in lymphocyte infiltration, leading to increased survival of tumor-bearing mice. Pharmacologic inhibition of chemokine receptors CCR1 and CCR5 resulted in extended survival and decreased myeloid cell infiltration. This work establishes the tumor-promoting role of myeloid cells in DMG and the potential therapeutic opportunities for targeting them. [Display omitted] •Driver mutations and tumor location shape the immune composition of high-grade gliomas•Immune-suppressive disease-associated myeloid cells are enriched in H3.3K27M DMG•Myeloid-derived CCL8 and CCL12 skew microglia toward disease-associated phenotypes•CCR1 and CCR5 inhibition reduces TAM infiltration and extends survival in DMG The role of tumor-associated macrophages (TAMs) in pediatric high-grade glioma (pHGG) remains highly understudied. Ross et al. find that tumor driver mutations uniquely shape the immune infiltrate and transcriptional profiles of TAMs. Interferon signaling in TAMs is critical for the anti-tumor immune response, and TAMs can be phenotypically skewed or pharmacologically inhibited for enhanced anti-tumor immunity.