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

in Immunity by James L Ross, Montserrat Puigdelloses-Vallcorba, Gonzalo Piñero, Nishant Soni, Wes Thomason, John DeSisto, Angelo Angione, Nadejda M Tsankova, Maria G Castro, Matthew Schniederjan, Nitin R Wadhwani, G Praveen Raju, Peter Morgenstern, Oren J Becher, Adam L Green, Alexander M Tsankov, Dolores Hambardzumyan

TLDR

  • This study looked at the role of myeloid cells in a type of brain tumor called pediatric high-grade gliomas (pHGGs) and diffuse midline gliomas (DMGs). The study found that myeloid cells are the main non-cancer cells in these tumors and that they help the tumor grow. The study also found that there are specific types of myeloid cells that are more likely to be found in these tumors. The study tested different ways to target these myeloid cells and found that it could help the tumor shrink and survive longer. This study could help doctors find new ways to treat these types of brain tumors.

Abstract

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.

Overview

  • The study investigates the role of myeloid cells in pediatric high-grade gliomas (pHGGs) and diffuse midline gliomas (DMGs).
  • The study uses immunocompetent de novo mouse models of pHGGs to demonstrate that myeloid cells are the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrate the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics are identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrate enrichment of DAMs. Genetic ablation of chemokines Ccl8 and Ccl12 results 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 results in extended survival and decreased myeloid cell infiltration.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies that myeloid cells are the predominant infiltrating non-neoplastic cell population in pHGGs and DMGs. The study also identifies disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrate enrichment of DAMs. Genetic ablation of chemokines Ccl8 and Ccl12 results 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 results in extended survival and decreased myeloid cell infiltration.

Implications and Future Directions

  • The study's findings suggest that myeloid cells play a tumor-promoting role in DMG and pHGGs. The study also identifies potential therapeutic opportunities for targeting myeloid cells in these tumors. Future research could explore the use of other chemokine inhibitors or targeting other myeloid cell subsets to further improve treatment outcomes.
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