%0 Journal Article
%A Xing, Yao Lulu
%A Panovska, Dena
%A Park, Jong-Whi
%A Grossauer, Stefan
%A Koeck, Katharina
%A Bui, Brandon
%A Nasajpour, Emon
%A Nirschl, Jeffrey J
%A Feng, Zhi-Ping
%A Cheung, Pierre
%A Habib, Pardes
%A Wei, Ruolun
%A Wang, Jie
%A Thomason, Wes
%A Monje, Michelle
%A Xiu, Joanne
%A Beck, Alexander
%A Weber, Katharina
%A Harter, Patrick N
%A Lim, Michael
%A Mahaney, Kelly B
%A Prolo, Laura M
%A Grant, Gerald A
%A Ji, Xuhuai
%A Walsh, Kyle M
%A Mulcahy Levy, Jean M
%A Hambardzumyan, Dolores
%A Petritsch, Claudia K
%T BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAFV600E-mutant glioma.
%J Cell reports / Medicine
%V 6
%N 6
%@ 2666-3791
%C Cambridge, MA
%I Cell Press
%M DKFZ-2025-01212
%P 102183
%D 2025
%Z 2025 Jun 17;6(6):102183
%X Resistance to v-raf murine sarcoma viral oncogene homolog B1 (BRAF) plus mitogen-activated protein kinase kinase (MEK) inhibition (BRAFi+MEKi) in BRAFV600E-mutant gliomas drives rebound, progression, and high mortality, yet it remains poorly understood. This study addresses the urgent need to develop treatments for BRAFi+MEKi-resistant glioma using preclinical mouse models and patient-derived materials. BRAFi+MEKi reveals glioma plasticity by heightening cell state transitions along glial differentiation trajectories, giving rise to astrocyte- and immunomodulatory oligodendrocyte (OL)-like states. PD-L1 upregulation in OL-like cells links cell state transitions to immune evasion, possibly orchestrated by Galectin-3. BRAFi+MEKi induces interferon response signatures, tumor infiltration, and suppression of T cells. Combining BRAFi+MEKi with immune checkpoint inhibition enhances survival in a T cell-dependent manner, reinvigorates T cells, and outperforms individual or sequential therapies in mice. Elevated PD-L1 expression in BRAF-mutant versus BRAF-wild-type glioblastoma supports the rationale for PD-1 inhibition in patients. These findings underscore the potential of targeting glioma plasticity and highlight combination strategies to overcome therapy resistance in BRAFV600E-mutant high-grade glioma.
%K BRAF V600E (Other)
%K BRAF and MEK inhibitor adaptation (Other)
%K Galectin-3 (Other)
%K T cell modulation (Other)
%K cell state transitions (Other)
%K high-grade glioma (Other)
%K immune checkpoint inhibition (Other)
%K programmed death-ligand 1 (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40505659
%R 10.1016/j.xcrm.2025.102183
%U https://inrepo02.dkfz.de/record/302014