PTEN Hemizygosity Drives Lower DNA Methylation, Immune Suppression, and Aggressive Behavior in IDH1-Mutant Astrocytomas

Abstract

Isocitrate dehydrogenase 1-mutant (IDH1m) astrocytomas, which generate the oncometabolite D-2-hydroxyglutarate (D-2HG), exhibit significant molecular heterogeneity, and understanding the molecular mechanisms underlying their behavior is crucial for devising effective therapeutic strategies. Here, we present an integrated molecular analysis that focuses on the impact of PTEN hemizygosity on IDH1m astrocytomas, an aggressive subset of these tumors that display genomic hypomethylation. First, we use a variety of models to show that PTEN reduction increases tumor growth and proliferation through activation of PI3K-AKT signaling. We then show that PTEN deletion increases expression of D-2-hydroxyglutarate dehydrogenase (D-2HGDH), which breaks down D-2HG into alpha ketoglutarate (aKT) to induce genomic hypomethylation. These hypomethylated regions are enriched for genes that orchestrate neurodevelopment and various immune processes, raising the possibility that PTEN hemizygosity alters the tumor microenvironment. We go on to show that PTEN reduction increases expression of Programmed death-ligand 1 (PD-L1), and that targeting Programmed cell death protein 1 (PD-1) using monoclonal antibody prolongs the survival of PTEN+/- murine allografts. Moreover, PTEN deletion promotes T cell infiltration, and PTEN+/- conditioned media induces an exhaustion phenotype in naïve CD8+ T cells. Lastly, we use an intracranial orthotopic injection model to show that inhibiting PI3K-AKT signaling in vivo prolongs the median survival of PTEN+/- tumors, and that combining this therapy with IDH1m inhibition is even more effective. Together, these data demonstrate that PTEN hemizygosity in IDH1m astrocytomas induce dramatic changes to DNA and histone methylation that result in (1) more aggressive behavior, and (2) alterations to the TME. These findings help to unravel the mechanisms driving tumor growth in PTEN-hemizygous IDH1m astrocytomas. They provide valuable insights into these tumors’ aggressive behavior and the profound alterations to the epigenetic landscape and the TME, as well as into new and promising therapeutic avenues.