Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Program for Mathematical Genomics, Columbia University, New York, NY 10032, USA.
Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Cell. 2022 Jul 7;185(14):2591-2608.e30. doi: 10.1016/j.cell.2022.06.007.
Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOXCD8 T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.
黑色素瘤脑转移（MBM）常发生于晚期黑色素瘤患者中；然而，我们对其潜在的显著生物学特性的理解还很初级。在此，我们对 22 例未经治疗的 MBM 和 10 例颅外黑色素瘤转移（ECM）以及匹配的空间单细胞转录组学和 T 细胞受体（TCR）-seq 进行了单细胞/核 RNA-seq 分析。MBM 中的癌细胞具有更高的染色体不稳定性，采用神经元样细胞状态，并富含空间差异表达的代谢途径。关键观察结果在独立的患者队列、患者来源的 MBM/ECM 异种移植模型、RNA/ATAC-seq、蛋白质组学和多重成像中得到了验证。整合的空间分析揭示了潜在的癌症免疫逃逸的不同地理区域，并为 MBM 中淋巴聚集物中 B 细胞向浆细胞分化的更多内肿瘤证据提供了依据。MBM 中存在更大比例的单核细胞衍生的巨噬细胞和功能失调的 TOXCD8 T 细胞，其免疫检查点表达也不同。这项工作提供了对 MBM 生物学的全面了解，并为进一步的发现和治疗探索提供了基础资源。
