Journal Article

DKFZ-2025-01212

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAFV600E-mutant glioma.

Xing, Y. L. ; Panovska, D. ; Park, J.-W. ; Grossauer, S. ; Koeck, K. ; Bui, B. ; Nasajpour, E. ; Nirschl, J. J. ; Feng, Z.-P. ; Cheung, P. ; Habib, P. ; Wei, R. ; Wang, J. ; Thomason, W. ; Monje, M. ; Xiu, J. ; Beck, A. ; Weber, K.DKFZ* ; Harter, P. N. ; Lim, M. ; Mahaney, K. B. ; Prolo, L. M. ; Grant, G. A. ; Ji, X. ; Walsh, K. M. ; Mulcahy Levy, J. M. ; Hambardzumyan, D. ; Petritsch, C. K.

2025
Cell Press Cambridge, MA

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Please use a persistent id in citations: doi:10.1016/j.xcrm.2025.102183

Abstract: 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.

Keyword(s): BRAF V600E ; BRAF and MEK inhibitor adaptation ; Galectin-3 ; T cell modulation ; cell state transitions ; high-grade glioma ; immune checkpoint inhibition ; programmed death-ligand 1

Note: 2025 Jun 17;6(6):102183

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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