文章目录

MCSP+转移创始细胞在人类黑色素瘤转移定植早期激活免疫抑制

原文发布日期：2025-05-16

英文摘要：

摘要翻译：

原文链接：

文章：

MCSP+转移创始细胞在人类黑色素瘤转移定植早期激活免疫抑制

MCSP+ metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization

原文发布日期：2025-05-16

英文摘要：

To investigate the early, poorly understood events driving metastatic progression, we searched for the earliest detectable disseminated cancer cells (DCCs), also often referred to as disseminated tumor cells (DTCs), in sentinel lymph node (SLN) biopsies of 492 patients with stage I–III melanoma. Using micromanipulator-assisted isolation of rare DCCs, single-cell mRNA and DNA sequencing, codetection by indexing immunofluorescence imaging and survival analysis, we identified melanoma-associated chondroitin sulfate proteoglycan (MCSP)+ melanoma cells as metastasis founder cells (MFCs). We found that DCCs entering SLNs predominantly exhibited a transitory phenotype that, upon interferon-γ exposure triggered by CD8 T cells, dedifferentiated into a neural-crest-like phenotype. This was accompanied by increased production of small extracellular vesicles (sEVs) carrying the immunomodulatory proteins CD155 and CD276 but rarely programmed cell death protein 1 ligand 1. The sEVs suppressed CD8 T cell proliferation and function, facilitating colony formation. Targeting MCSP+ MFCs or their immune escape mechanisms could be key to curing melanoma early by preventing manifestation of metastasis.

摘要翻译：

为了研究驱动转移进展的早期、尚不完全理解的事件，我们筛选了492例I-Ⅲ期黑色素瘤患者的Sentinella淋巴结穿刺材料中的最早可检测到的分散癌细胞（DCCs），这些细胞有时也被称为分散肿瘤细胞（DTC）。通过使用微操作辅助分离罕见DCC、单细胞mRNA和DNA测序、免疫荧光成像指数编码以及生存分析等方法，我们识别出黑色素瘤相关的带硫酸交联蛋白的糖蛋白（MCSP）+黑色素瘤细胞作为转移始祖细胞（MFC）。我们发现，进入淋巴结的DCCs大多表现出一种暂时性表型，在受到干扰素γ刺激（由CD8 T细胞引发时），会发生向神经 crest-like表型的分化。这伴随大量产生携带免疫调节蛋白CD155和CD276的小细胞外基质（sEVs）以及罕见的程序性死亡蛋白1亲本结合蛋白1。这些sEVs抑制了CD8 T细胞的增殖和功能，从而促进了瘤团的形成。靶向MCSP+ MFC及其免疫逃避机制可能是早期治愈黑色素瘤的关键，通过阻止转移表现的发生。