Abstract Pediatric high-grade glioma (pHGG) is a devastating and uniformly fatal disease. pHGGs with BRAF mutations have been associated with increased intratumoral CD8+ T cells which display clonal expansion and effector properties, suggestive of a T cell-mediated anti-tumor activity. Combined BRAF and MEK inhibition (BRAFi+MEKi) is routinely used to treat BRAF-mutant HGGs and outperforms chemotherapy. However, approximately 70% of BRAF-mutantV600E HGG patients fail to respond to BRAFi+MEKi and undergo unbridled tumor progression. Owing to the lack of patient material after treatment, the effect of BRAFi+MEKi on tumor-intrinsic signaling mechanisms and tumor-associated T-cell interactions is unclear. Using patient-matched tumor tissue from before and after BRAFi+MEKi, we unraveled increased glial differentiation and upregulation of programmed cell death protein-1 (PD-1) ligand (PD-L1) as an adaptation and potential escape mechanism to treatment. In two patient-derived cell lines, we confirmed that BRAFi+MEKi induced glial differentiation and PD-L1 up-expression. Multiplexed, high-resolution secretome analysis identified significant in vitro upregulation of Galectin-3, and down regulation of interleukin- 6 and -8 in response to BRAFi+MEKi treatment. Currently, the direct influence of Galectin-3 on tumor behavior and T-cell function is under investigation. Galectin-3 treatment might promote differentiated glioma phenotypes and robust PD-L1 expression. In parallel, Galectin-3 might profoundly impact T-cell function, by driving increased apoptosis, suppressed proliferation, and diminished interferon-gamma signatures, highlighting its role in fostering an immunosuppressive tumor microenvironment. As such, this research effort aims at providing a link between T-cell immunosuppression and glial differentiation, governed by BRAFi+MEKi treatment. In conclusion, dual BRAF and MAPK inhibition may trigger Galectin-3 secretion, which could serve as a tumor escape mechanism.
Panovska et al. (Fri,) studied this question.