BIOL-05. MAPK PATHWAY INHIBITION SENSITIZES TO IMMUNOTHERAPY IN BRAF-MUTANT GLIOMAS

Abstract

BackgroundBRAF alterations frequently occur in pediatric low-grade gliomas. Previously, we showed that dabrafenib and trametinib (D+T) that target MAPK pathway can mediate the antitumor effect in a preclinical model of BRAF-mutant glioma (PMC5342782). Here, we further investigate the effect of MAPK pathway inhibitors on cancer cells and tumor-infiltrating immune cells to maximize the therapeutic efficacy in malignant gliomas. MethodsDrug concentrations in tumor, brain and plasma were assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RNA sequencing and Gene Set Enrichment Analysis were performed using patient-derived BRAF-mutant glioma lines upon D+T treatment. Molecular profiles of drug-resistant clones were assessed for understanding of glioma heterogeneity and exploring new therapeutic targets. Results. BRAF-mutant stem-like glioma cells were particularly resistant to BRAF or MAPK inhibitor, along with aggressive phenotype in mice. LC-MS/MS showed effective D+T drug delivery in tumor regions. The transcriptome analysis demonstrated that D+T upregulate HLA molecules and downregulate immunosuppressive factors in patient-derived BRAF-mutant glioma lines. Consistent with these molecular changes, D+T led to changes in the proportions of tumor-infiltrating immune cells, including CD8+ cytotoxic T lymphocytes and FOXP3+ regulatory T cells. Furthermore, the therapeutic effect of D+T was further enhanced in combination with immune checkpoint inhibition. ConclusionsThe present study highlights the immunomodulatory activity of MAPK pathway inhibitors in BRAF-mutant gliomas.