美国哥伦比亚大学Benjamin Izar小组解析未经治疗型人类黑色素瘤脑转移的生态系统。这一研究成果发表在2022年7月7日出版的国际学术期刊《细胞》上。
研究人员对22个未经治疗的黑色素瘤脑转移（MBM）和10个颅外黑色素瘤转移瘤（ECM）进行了单细胞/细胞核RNA-seq，并对空间单细胞转录组学和T细胞受体（TCR）-seq进行了匹配。来自MBM的癌细胞在染色体上更不稳定，采用了类似神经元的细胞状态，并富含空间上不同表达的代谢途径。关键观察结果在独立的患者队列、患者衍生的MBM/ECM异种移植模型、RNA/ATAC-seq、蛋白质组学和多重成像中得到验证。
综合空间分析显示，推测的癌症免疫逃逸具有不同的区域分布，并有证据表明MBM的淋巴细胞聚集区有更丰富的瘤内B细胞到浆细胞的分化过程。MBM藏有更多的单核细胞衍生的巨噬细胞和功能失调的TOX+CD8+T细胞，并有免疫检查点的不同表达。这项工作提供了对MBM生物学的全面见解，并作为进一步发现和探索治疗的基础资源。
据介绍，MBM经常发生在晚期黑色素瘤患者身上；然而，人们对潜在的突出生物学的理解还很不成熟。
附：英文原文
Title: Dissecting the treatment-naive ecosystem of human melanoma brain metastasis
Author: Jana Biermann, Johannes C. Melms, Amit Dipak Amin, Yiping Wang, Lindsay A. Caprio, Alcida Karz, Somnath Tagore, Irving Barrera, Miguel A. Ibarra-Arellano, Massimo Andreatta, Benjamin T. Fullerton, Kristjan H. Gretarsson, Varun Sahu, Vaibhav S. Mangipudy, Trang T.T. Nguyen, Ajay Nair, Meri Rogava, Patricia Ho, Peter D. Koch, Matei Banu, Nelson Humala, Aayushi Mahajan, Zachary H. Walsh, Shivem B. Shah, Daniel H. Vaccaro, Blake Caldwell, Michael Mu, Florian Wünnemann, Margot Chazotte, Simon Berhe, Adrienne M. Luoma, Joseph Driver, Matthew Ingham, Shaheer A. Khan, Suthee Rapisuwon, Craig L. Slingluff, Thomas Eigentler, Martin Rcken, Richard Carvajal, Michael B. Atkins, Michael A. Davies, Albert Agustinus, Samuel F. Bakhoum, Elham Azizi, Markus Siegelin, Chao Lu, Santiago J. Carmona, Hanina Hibshoosh, Antoni Ribas, Peter Canoll, Jeffrey N. Bruce, Wenya Linda Bi, Praveen Agrawal, Denis Schapiro, Eva Hernando, Evan Z. Macosko, Fei Chen
Issue&Volume: 2022/07/07
Abstract: Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma;yet, our understanding of the underlying salient biology is rudimentary. Here, weperformed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranialmelanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cellreceptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopteda neuronal-like cell state, and enriched for spatially variably expressed metabolicpathways. Key observations were validated in independent patient cohorts, patient-derivedMBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integratedspatial analyses revealed distinct geography of putative cancer immune evasion andevidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoidaggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages anddysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensiveinsights into MBM biology and serves as a foundational resource for further discoveryand therapeutic exploration.
DOI: 10.1016/j.cell.2022.06.007
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00712-7