BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAFV600E-mutant glioma

Yao Lulu Xing; Dena Panovska; Jong-Whi Park; Stefan Grossauer; Katharina Koeck; Brandon Bui; Emon Nasajpour; Jeffrey J Nirschl; Zhi-Ping Feng; Pierre Cheung; Pardes Habib; Ruolun Wei; Jie Wang; Wes Thomason; Michelle Monje; Joanne Xiu; Alexander Beck; Katharina J Weber; Patrick N Harter; Michael Lim; Kelly B Mahaney; Laura M Prolo; Gerald A Grant; Xuhuai Ji; Kyle M Walsh; Jean M Mulcahy Levy; Dolores Hambardzumyan; Claudia K Petritsch

doi:10.1016/j.xcrm.2025.102183

BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAF^V600E-mutant glioma

Cell Rep Med. 2025 Jun 17;6(6):102183. doi: 10.1016/j.xcrm.2025.102183. Epub 2025 Jun 12.

Authors

Yao Lulu Xing¹, Dena Panovska¹, Jong-Whi Park², Stefan Grossauer³, Katharina Koeck⁴, Brandon Bui¹, Emon Nasajpour¹, Jeffrey J Nirschl⁵, Zhi-Ping Feng⁶, Pierre Cheung⁷, Pardes Habib¹, Ruolun Wei¹, Jie Wang⁷, Wes Thomason⁸, Michelle Monje⁹, Joanne Xiu¹⁰, Alexander Beck¹¹, Katharina J Weber¹², Patrick N Harter¹¹, Michael Lim¹, Kelly B Mahaney¹, Laura M Prolo¹, Gerald A Grant¹³, Xuhuai Ji¹⁴, Kyle M Walsh¹⁵, Jean M Mulcahy Levy¹⁶, Dolores Hambardzumyan⁸, Claudia K Petritsch¹⁷

Affiliations

¹ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Life Sciences, Gachon University, Incheon 21999, South Korea.
³ Vienna Medical Center, Medical University of Vienna, Vienna 1090, Austria.
⁴ Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna 1090, Austria.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ The Australian National University Bioinformatics Consultancy, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2600, Australia.
⁷ Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Department of Oncological Sciences and Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
¹⁰ Medical Affairs, Caris Life Sciences Inc, Phoenix, AZ 85040, USA.
¹¹ Center for Neuropathology and Prion Research, Faculty of Medicine, Ludwig-Maximilians-University, 80539 Munich, Germany.
¹² Goethe University Frankfurt, University Hospital, Neurological Institute (Edinger Institute) and University Cancer Center (UCT), 60629 Frankfurt am Main, Germany; Frankfurt Cancer Institute, 60629 Frankfurt am Main, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
¹³ Department of Neurosurgery, Duke University, Durham, NC 27708, USA.
¹⁴ Human Immune Monitoring Centre, Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA 94305, USA.
¹⁵ Division of Neuro-Epidemiology, Department of Neurosurgery, Duke University, Durham, NC 27708, USA.
¹⁶ Morgan Adams Foundation Brain Tumor Research Program, Department of Pediatrics, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO 80045, USA.
¹⁷ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Maternal & Child Health Research Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: clpetritsch39@gmail.com.

Abstract

Resistance to v-raf murine sarcoma viral oncogene homolog B1 (BRAF) plus mitogen-activated protein kinase kinase (MEK) inhibition (BRAFi+MEKi) in BRAF^V600E-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 BRAF^V600E-mutant high-grade glioma.

Keywords: 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.

MeSH terms

Animals
B7-H1 Antigen / metabolism
Brain Neoplasms* / drug therapy
Brain Neoplasms* / genetics
Brain Neoplasms* / immunology
Brain Neoplasms* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Glioma* / drug therapy
Glioma* / genetics
Glioma* / immunology
Glioma* / pathology
Humans
Immune Checkpoint Inhibitors* / pharmacology
Mice
Mitogen-Activated Protein Kinase Kinases* / antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases* / metabolism
Mutation
Protein Kinase Inhibitors* / pharmacology
Protein Kinase Inhibitors* / therapeutic use
Proto-Oncogene Proteins B-raf* / antagonists & inhibitors
Proto-Oncogene Proteins B-raf* / genetics
Proto-Oncogene Proteins B-raf* / metabolism

Substances

Proto-Oncogene Proteins B-raf
Protein Kinase Inhibitors
B7-H1 Antigen
BRAF protein, human
Mitogen-Activated Protein Kinase Kinases
Immune Checkpoint Inhibitors
CD274 protein, human

Abstract

MeSH terms

Substances

Grants and funding