DKK1+ 肿瘤细胞抑制了 CCL19+ 成纤维细胞和浆细胞的浸润,从而导致肝细胞癌的免疫治疗反应更差。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Guangyu Fan, Ruyun Gao, Tongji Xie, Lin Li, Le Tang, Xiaohong Han, Yuankai Shi
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引用次数: 0

摘要

在肝细胞癌(HCC)中,瘤内免疫浸润在与肿瘤细胞的相互作用中起着关键作用。然而,其表型和相关的空间结构仍然难以捉摸。为了解决这些局限性,我们结合空间数据(来自 8 个样本的 38,191 个点)和单细胞数据(来自 20 个样本的 56,022 个细胞)进行了一项综合研究。我们的分析揭示了两种不同的浸润模式:免疫排斥和免疫激活。浆细胞是肿瘤内免疫集群的主要细胞类型。值得注意的是,我们观察到 CCL19+ 成纤维细胞与浆细胞共定位,浆细胞分泌趋化因子,促进 T 细胞活化和白细胞迁移。相反,在免疫排斥样本中,这种共定位主要出现在邻近的正常区域。这种共定位与 T 细胞浸润和三级淋巴结构的形成有关,对 20 个 HCC 样本进行的多重免疫荧光验证了这一点。CCL19+成纤维细胞和浆细胞都与良好的生存结果有关。在免疫疗法队列中,反应良好的 HCC 患者表现出较高的 CCL19+ 成纤维细胞和浆细胞浸润。此外,在免疫排斥样本中,我们观察到 DKK1+ 肿瘤细胞在肿瘤区域内聚集,尤其是在肿瘤边界,这抑制了 CCL19+ 成纤维细胞和浆细胞向肿瘤区域的浸润。此外,在免疫排斥样本中,SPP1 信号通路在肿瘤和免疫集群之间的通讯中表现出最高的活性,而 CCL19-CCR7 在免疫集群的自我通讯中起着关键作用。这项研究阐明了HCC的免疫排斥和免疫激活模式,并确定了导致免疫抵抗的相关因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
DKK1+ tumor cells inhibited the infiltration of CCL19+ fibroblasts and plasma cells contributing to worse immunotherapy response in hepatocellular carcinoma.

Intra-tumor immune infiltration plays a pivotal role in the interaction with tumor cells in hepatocellular carcinoma (HCC). However, its phenotype and related spatial structure remained elusive. To address these limitations, we conducted a comprehensive study combining spatial data (38,191 spots from eight samples) and single-cell data (56,022 cells from 20 samples). Our analysis revealed two distinct infiltration patterns: immune exclusion and immune activation. Plasma cells emerged as the primary cell type within intra-tumor immune clusters. Notably, we observed the co-location of CCL19+ fibroblasts with plasma cells, which secrete chemokines and promote T-cell activation and leukocyte migration. Conversely, in immune-exclusion samples, this co-location was primarily observed in the adjacent normal area. This co-localization correlated with T cell infiltration and the formation of tertiary lymphoid structures, validated by multiplex immunofluorescence conducted on twenty HCC samples. Both CCL19+ fibroblasts and plasma cells were associated with favorable survival outcomes. In an immunotherapy cohort, HCC patients who responded favorably exhibited higher infiltration of CCL19+ fibroblasts and plasma cells. Additionally, we observed the accumulation of DKK1+ tumor cells within the tumor area in immune-exclusion samples, particularly at the tumor boundary, which inhibited the infiltration of CCL19+ fibroblasts and plasma cells into the tumor area. Furthermore, in immune-exclusion samples, the SPP1 signaling pathway demonstrated the highest activity in communication between tumor and immune clusters, and CCL19-CCR7 played a pivotal role in the self-communication of immune clusters. This study elucidates immune exclusion and immune activation patterns in HCC and identifies relevant factors contributing to immune resistance.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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