文章：

细胞融合上调PD-L1表达以逃避免疫监视

Cell fusion upregulates PD-L1 expression for evasion from immunosurveillance 

原文发布日期：2023-11-21 

英文摘要：

MSCs (mesenchymal stem cells), responsible for tissue repair, rarely undergo cell fusion with somatic cells. Here, we show that ~5% of bladder cancer cells (UMUC-3) fuses with bone marrow-derived MSC (BM-MSC) in co-culture and maintains high tumorigenicity. In eleven fusion cell clones that have been established, Mb-scale deletions carried by the bladder cancer cells are mostly absent in the fusion cells, but copy number gains contributed by the cancer cells have stayed. Fusion cells exhibit increased populations of mitotic cells with 3-polar spindles, indicative of genomic instability. They grow faster in vitro and exhibit higher colony formation in anchorage-independent growth assay in soft agar than the parent UMUC-3 does. Fusion cells develop tumors, after 4 weeks of time lag, as efficiently as the parent UMUC-3 does in xenograft experiments. 264 genes are identified whose expression is specifically altered in the fusion cells. Many of them are interferon-stimulated genes (ISG), but are activated in a manner independent of interferon. Among them, we show that PD-L1 is induced in fusion cells, and its knockout decreases tumorigenesis in a xenograft model. PD-L1 is induced in a manner independent of STAT1 known to regulate PD-L1 expression, but is regulated by histone modification, and is likely to inhibit phagocytosis by PD1-expressing macrophages, thus protecting cancer cells from immunological attacks. The fusion cells overexpress multiple cytokines including CCL2 that cause tumor progression by converting infiltrating macrophages to tumor-associated-macrophage (TAM). The results present mechanisms of how cell fusion promotes tumorigenesis, revealing a novel link between cell fusion and PD-L1, and underscore the efficacy of cancer immunotherapy. 

摘要翻译： 

间充质干细胞（MSCs）主要负责组织修复，很少与体细胞发生融合。本研究发现，在共培养体系中约5%的膀胱癌细胞（UMUC-3）会与骨髓来源的MSCs（BM-MSCs）发生融合，且融合细胞仍保持高致瘤性。在建立的11个融合细胞克隆中，膀胱癌细胞携带的百万碱基规模缺失在融合细胞中大多消失，但癌细胞贡献的拷贝数增加得以保留。融合细胞表现出更多具有三极纺锤体的有丝分裂细胞，提示基因组不稳定性。相较于亲本UMUC-3，融合细胞在体外增殖更快，并在软琼脂锚定非依赖性生长试验中形成更多集落。在异种移植实验中，融合细胞虽延迟4周形成肿瘤，但成瘤效率与亲本UMUC-3相当。研究鉴定出264个在融合细胞中特异性表达改变的基因，其中多数为干扰素刺激基因（ISG），但其激活不依赖干扰素通路。我们证明PD-L1在融合细胞中被诱导表达，其基因敲除可降低异种移植模型的肿瘤发生。PD-L1的诱导不依赖于已知调控其表达的STAT1通路，而是受组蛋白修饰调控，并可能通过抑制表达PD1的巨噬细胞的吞噬作用来保护癌细胞免受免疫攻击。融合细胞过度表达CCL2等多种细胞因子，通过将浸润巨噬细胞转化为肿瘤相关巨噬细胞（TAM）促进肿瘤进展。这些结果揭示了细胞融合促进肿瘤发生的新机制——建立了细胞融合与PD-L1表达的新关联，并印证了癌症免疫疗法的有效性。

原文链接：

Cell fusion upregulates PD-L1 expression for evasion from immunosurveillance