Clinically relevant concurrent BRAF and MEK inhibition alters differentiation states and sensitizes BRAF V600E-mutated high-grade gliomas to immune checkpoint blockade

Abstract

ABSTRACTBRAF V600E-mutated glioma patients are in urgent need of new treatments, since standard chemoradiotherapy and surgery achieves tumor control in less than 30% of patients. BRAF and MEK inhibitor combinations have shown promising results against several types of BRAF V600E mutated cancers. Patients with high-grade BRAF V600E mutated gliomas frequently experience therapy failure with concurrent BRAF V600E and MEK inhibition (BRAFi+MEKi). Overcoming therapy resistance begins with understanding how these inhibitors affect tumor cells and the immune microenvironment. In novel syngeneic murine models and patient-derived cell lines of BRAF V600E-mutated high-grade astrocytomas, we analyzed effects of BRAF V600E expression and BRAF V600E inhibitor Dabrafenib and MEK inhibitor Trametinib (BRAFi+MEKi). BRAF V600E expression disrupted asymmetric cell division and glial differentiation, and BRAFi+MEKi restored these defects, and enriched for potentially therapy resistant CD133+ tumor cells. Increased interferon alpha and gamma signatures and pro-inflammatory cytokines were detected. Programmed death (PD-1) receptor ligand was found to be expressed in murine and human BRAF V600E mutated high-grade gliomas, and BRAFi+MEKi upregulated the frequency of tumor-infiltrating T cells expressing inhibitory immune checkpoints, suggestive of T cell exhaustion. Combining dual MAPK pathway with immune checkpoint inhibition by anti-PD-L1 and anti-CTLA-4 treatment decreased T cell deactivation and resulted in a T cell-dependent survival benefit of mice with orthotopic BRAF V600E-mutated high-grade gliomas. These data showed that clinically relevant dual MAPK pathway inhibition sensitized high-grade gliomas to the anti-tumor activity of concurrent dual immune checkpoint blockades. Therefore, we propose that in patients with BRAF V600E high-grade gliomas, improved therapeutic benefits could be derived from combining BRAFi+MEKi with immune checkpoint inhibitors.