Xing Yao Lulu, Panovska Dena, Park Jong-Whi, Grossauer Stefan, Koeck Katharina, Bui Brandon, Nasajpour Emon, Nirschl Jeffrey J, Feng Zhi-Ping, Cheung Pierre, Habib Pardes, Wei Ruolun, Wang Jie, Thomason Wes, Xiu Joanne, Beck Alexander, Weber Katharina, Harter Patrick N, Lim Michael, Mahaney Kelly, Prolo Laura M, Grant Gerald A, Ji Xuhuai, Walsh Kyle M, Mulcahy Levy Jean M, Hambardzumyan Dolores, Petritsch Claudia Katharina
bioRxiv. 2025 Apr 1:2023.02.03.526065. doi: 10.1101/2023.02.03.526065.
Resistance to BRAF plus 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 in novel 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 tumor 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-wildtype 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 HGG.
BRAFV600E 突变型胶质瘤对 BRAF 加 MEK 抑制（BRAFi+MEKi）产生耐药会导致病情反弹、进展和高死亡率，但对此仍知之甚少。本研究满足了在新型小鼠模型和患者来源材料中开发针对 BRAFi+MEKi 耐药性胶质瘤治疗方法的迫切需求。BRAFi+MEKi 通过增强沿神经胶质细胞分化轨迹的细胞状态转变来揭示胶质瘤可塑性，从而产生星形胶质细胞样和免疫调节性少突胶质细胞（OL）样状态。OL 样细胞中 PD-L1 的上调将细胞状态转变与肿瘤逃避联系起来，这可能是由半乳糖凝集素-3 精心策划的。BRAFi+MEKi 诱导干扰素反应特征、肿瘤浸润并抑制 T 细胞。将 BRAFi+MEKi 与免疫检查点抑制相结合以 T 细胞依赖的方式提高生存率，重振 T 细胞，并且在小鼠中优于单独或序贯疗法。BRAF 突变型与 BRAF 野生型胶质母细胞瘤中 PD-L1 表达升高支持了在患者中进行 PD-1 抑制的理论依据。这些发现强调了靶向胶质瘤可塑性的潜力，并突出了克服 BRAFV600E 突变型高级别胶质瘤治疗耐药性的联合策略。
