RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
早期与晚期结直肠癌中三级淋巴结构的动态变化及免疫交互作用：对免疫治疗的潜在意义
英文原题：Dynamics of tertiary lymphoid structures and immune cross talk in early versus advanced colorectal cancer: potential implications for immunotherapy.
查看英文原题
Dynamics of tertiary lymphoid structures and immune cross talk in early versus advanced colorectal cancer: potential implications for immunotherapy.
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研究概要
我们的研究揭示了晚期 CRC 中多层次的免疫功能障碍，并阐明了 CRC 进展过程中 TLS 的变化，为晚期 CRC 的功能研究和潜在靶点的探索提供了见解。
研究思路结论见上方概要
背景
无论微卫星状态如何，免疫检查点抑制剂治疗在早期结直肠癌（CRC）中比晚期病例显示出更优的疗效。早期和晚期CRC之间肿瘤微环境（TME）和三级淋巴结构（TLS）的差异可能是一个关键因素，但仍未完全阐明。
方法
我们全面分析了单细胞RNA测序数据、批量RNA转录数据和病理组织数据，以探究TME的动态变化。利用三个内部队列，探讨了早期和晚期肿瘤中TLS的特征及其对免疫治疗的潜在影响。
结果
我们提供了早期和晚期CRC免疫景观的单细胞精细图谱。在早期和晚期CRC之间，CD4+ Tfh和BGC细胞中发现了显著的功能差异。我们揭示了CD8+ Tex细胞上的CXCL13表达，以及CD4+ Tfh和BGC细胞之间的CD40-CD40L相互作用，可能是TLS功能的关键调节因子，并进而影响免疫治疗的应答。
展开英文摘要原文
BACKGROUND
Irrespective of microsatellite status, immune checkpoint inhibitor therapy shows superior efficacy in early-stage colorectal cancer (CRC) compared to advanced cases. The distinctions of the tumor microenvironment (TME) and tertiary lymphoid structure (TLS) between early- and advanced-stage CRC may represent a critical factor, yet remain incompletely elucidated.
METHODS
We comprehensively analyzed single-cell RNA sequencing data, bulk RNA transcription data and pathological tissue data to investigate the dynamic changes in the TME. The features of TLS in early- and advanced-stage tumors and their potential impact on immunotherapy were explored using three in-house cohorts.
RESULTS
We provided single-cell fine maps of the immune landscape in early and advanced CRC. Significant functional differences were identified in CD4 + Tfh and BGC cells between early and advanced CRC. We revealed CXCL13 expression on CD8 + Tex cells, along with CD40-CD40L interactions between CD4 + Tfh and BGC cells, could be key regulators of TLS functionality and subsequently affect the response to immunotherapy.
CONCLUSIONS
Our research shed light on the multilayered immune dysfunction in advanced CRC and elucidates the alterations in the TLS during the progression of CRC, providing insights for functional studies and the exploration of potential target in advanced CRC.
论文信息
- 作者
- Chen Z、Hu B、Cai K、Gao H、Xian Z、Zhang S、Fang Z、Zhou Q
- 第一作者单位
- School of Basic Medical Sciences, Shandong Provincial Hospital, Shandong University, Jinan, 250012, Shandong, People's Republic of China.China
- 通讯作者单位
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250000, Shandong, People's Republic of China. zouq27@mail2.sysu.edu.cn.China
- 期刊
- Cancer immunology, immunotherapy : CII2025 Apr 26
- 原文标识
- PubMed 40287532 · DOI 10.1007/s00262-025-04027-x
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