Abstract
BACKGROUND
Despite successes, clinical MAPK pathway inhibitors show limited anti-tumor activity in the majority of patients with BRAF-mutant high-grade glioma. Because of the presence of higher fraction of CD8+ tumor-infiltrating T cells in MAPK pathway-altered glioma, we explored the possibility that combined BRAF and MEK inhibition with immune checkpoint blockade enhances anti-tumor response.
METHODS
We engineered mice to carry BRAF V600E expression and CDKN2A deletion in various hemispheric areas. We treated syngeneic tumor-bearing mice with dabrafenib, trametinib, anti-PD-L1 and anti-CTLA-4 antibodies, and analyzed the tumor immune infiltrate by high-dimensional single-cell mass cytometry (CyTOF). RNA sequencing and Gene Set Enrichment Analysis were conducted using patient-derived BRAF-mutant glioma lines upon the inhibitor treatment.
RESULTS
The transcriptome analysis demonstrated that antigen processing and presentation feature is strongly enriched upon dual MAPK pathway inhibition. Consistent with these molecular changes, dabrafenib and trametinib treatment led to dynamic changes in tumor-infiltrating immune cells, including CD8+ and CD4+ T cells. In line with this, combination of MAPK pathway and immune checkpoint inhibitors elicit a significant survival benefit over MAPK pathway inhibition alone in mice with orthotopic BRAF-mutant glioma.
CONCLUSIONS
Clinically relevant molecular targeted therapy by dabrafenib and trametinib and immune checkpoint blockade synergize in pre-clinical models.
PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models
