The development of brain metastases hallmarks disease progression in 20–40% of melanoma patients and is a serious obstacle to therapy. Understanding the processes involved in the development and maintenance of melanoma brain metastases (MBM) is critical for the discovery of novel therapeutic strategies. Here, we generated transcriptome and methylome profiles of MBM showing high or low abundance of infiltrated Iba1^high tumor-associated microglia and macrophages (TAMs). Our survey identified potential prognostic markers of favorable disease course and response to immune checkpoint inhibitor (ICi) therapy, among them APBB1IP and the interferon-responsive gene ITGB7. In MBM with high ITGB7/APBB1IP levels, the accumulation of TAMs correlated significantly with the immune score. Signature-based deconvolution of MBM via single sample GSEA revealed enrichment of interferon-response and immune signatures and revealed inflammation, stress and MET receptor signaling. MET receptor phosphorylation/activation maybe elicited by inflammatory processes in brain metastatic melanoma cells via stroma cell-released HGF. We found phospho-MET^Y1234/1235 in a subset of MBM and observed a marked response of brain metastasis-derived cell lines (BMCs) that lacked druggable BRAF mutations or developed resistance to BRAF inhibitors (BRAFi) in vivo to MET inhibitors PHA-665752 and ARQ197 (tivantinib). In summary, the activation of MET receptor in brain colonizing melanoma cells by stromal cell-released HGF may promote tumor self-maintenance and expansion and might counteract ICi therapy. Therefore, therapeutic targeting of MET possibly serves as a promising strategy to control intracranial progressive disease and improve patient survival.

脑转移的发生是 20-40% 黑色素瘤患者疾病进展的标志，也是治疗的严重障碍。了解黑色素瘤脑转移 (MBM) 的发展和维持过程对于发现新的治疗策略至关重要。在这里，我们生成了 MBM 的转录组和甲基化组图谱，显示了高或低丰度的浸润 Iba1^高肿瘤相关小胶质细胞和巨噬细胞 (TAM)。我们的调查确定了有利病程和对免疫检查点抑制剂 (ICi) 治疗反应的潜在预后标志物，其中包括APBB1IP和干扰素反应基因ITGB7。在ITGB7/APBB1IP水平较高的 MBM 中，TAM 的积累与免疫评分显着相关。通过单样本 GSEA 对 MBM 进行基于特征的解卷积，揭示了干扰素反应和免疫特征的富集，并揭示了炎症、应激和 MET 受体信号传导。MET 受体磷酸化/激活可能是由脑转移性黑色素瘤细胞中的炎症过程通过基质细胞释放的 HGF 引起的。我们在 MBM 的一个子集中发现了磷酸化 MET ^Y1234/1235，并观察到缺乏可药物 BRAF 突变或体内对 BRAF 抑制剂 (BRAFi) 产生耐药性的脑转移衍生细胞系 (BMC) 对 MET 抑制剂 PHA-665752 的显着反应和 ARQ197（替凡替尼）。总之，基质细胞释放的 HGF 激活大脑定植黑色素瘤细胞中的 MET 受体可能促进肿瘤的自我维持和扩张，并可能抵消 ICi 治疗。因此，MET 的治疗靶向可能是控制颅内进展性疾病和提高患者生存率的有前途的策略。