STINGing the immune system: lessons learned through a model of G34-mutant pediatric high-grade glioma

Abstract

Pediatric high-grade gliomas (pHGGs) are aggressive diseases with poor outcomes. The diverse molecular heterogeneity in these rare tumors and inadequate tumor models have limited the development of effective therapies. In this issue of the JCI, Haase et al. produced a genetically engineered mouse model of H3.3-G34R-mutant pHGG to help identify vulnerabilities in DNA repair pathways. The authors designed a therapy that combined radiation with DNA damage response inhibitors to induce an adaptive immune response and extend survival. These findings suggest that combinations of small-molecule therapies with immunotherapies could drive a more durable response and improve mortality for patients with pHGG.

Figure 1. Targeting vulnerabilities in DNA damage response pathways in G34R-mutant pHGG induces cell death and immunological memory.

DNA repair pathways are downregulated in G34R-mutant pHGGs, leading to increased DNA damage and activation of the cGAS/STING immune response. Radiation combined with DNA damage response inhibitors or a STING agonist leads to cell death and immunological memory, and extends survival in models of G34R-mutant pHGG. Chk1/2i, Chk1/2 inhibitor; PARPi, PARP inhibitor.