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从肠化生到早期胃癌的FOLR2巨噬细胞耗竭：单细胞测序洞察胃癌进展

FOLR2 macrophage depletion from intestinal metaplasia to early gastric cancer: single-cell sequencing insight into gastric cancer progression.

作者信息

He Yuxin, Wang Jiayu, Deng Zilin, Feng Huang, Du Mingzhan, Zhang Deqing, Zhang Guangbo, Shi Tongguo, Chen Weichang

机构信息

Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China.

Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China.

出版信息

J Exp Clin Cancer Res. 2024 Dec 19;43(1):326. doi: 10.1186/s13046-024-03245-y.

DOI:10.1186/s13046-024-03245-y
PMID:39702278
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11657096/
Abstract

BACKGROUND

The immune landscape associated with different subtypes of intestinal metaplasia (IM) and early gastric cancer (EGC) remains unclear. This study aimed to investigate the immune landscape of complete intestinal metaplasia (CIM), incomplete intestinal metaplasia (IIM), and EGC, as well as the underlying mechanisms of EGC progression.

METHODS

Gastric biopsy samples were collected from five patients with CIM, six patients with IIM, and four patients with EGC, followed by single-cell RNA sequencing. Multiplex immunohistochemical staining was employed to validate the samples from the aforementioned patients. To elucidate the potential mechanisms involved, in vitro coculture experiments were conducted using FOLR2/FOLR2 macrophages and CD8 T cells. Flow cytometry was utilized to investigate the biological functions of FOLR2 macrophages in the progression of EGC.

RESULTS

Five subpopulations of macrophages were identified in CIM, IIM and EGC samples. FOLR2 macrophages possess antitumor immune potential, and the proportion of FOLR2 macrophage gradually decreased from the CIM stage to the IIM and EGC stages. FOLR2 macrophages were significantly positively correlated with CD8 T cells and activated the cytotoxicity of CD8 T cells via antigen cross-presentation. Additionally, during the progression of EGC, epithelial cells progressively upregulated APP expression, thus inducing necroptosis of FOLR2 macrophages via the APP‒TNFRSF21 axis.

CONCLUSIONS

Our work provides an understanding of the potential mechanisms underlying the malignant transformation of IM mediated by FOLR2 macrophages.

摘要

背景

与不同亚型肠化生（IM）和早期胃癌（EGC）相关的免疫格局仍不清楚。本研究旨在调查完全性肠化生（CIM）、不完全性肠化生（IIM）和EGC的免疫格局，以及EGC进展的潜在机制。

方法

收集5例CIM患者、6例IIM患者和4例EGC患者的胃活检样本，随后进行单细胞RNA测序。采用多重免疫组化染色对上述患者的样本进行验证。为了阐明潜在的机制，使用FOLR2/FOLR2巨噬细胞和CD8 T细胞进行体外共培养实验。利用流式细胞术研究FOLR2巨噬细胞在EGC进展中的生物学功能。

结果

在CIM、IIM和EGC样本中鉴定出5个巨噬细胞亚群。FOLR2巨噬细胞具有抗肿瘤免疫潜力，FOLR2巨噬细胞的比例从CIM阶段到IIM和EGC阶段逐渐降低。FOLR2巨噬细胞与CD8 T细胞显著正相关，并通过抗原交叉呈递激活CD8 T细胞的细胞毒性。此外，在EGC进展过程中，上皮细胞逐渐上调APP表达，从而通过APP-TNFRSF21轴诱导FOLR2巨噬细胞发生坏死性凋亡。

结论

我们的工作揭示了FOLR2巨噬细胞介导的IM恶性转化的潜在机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/fe0e17fadc14/13046_2024_3245_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/5a2e71582c37/13046_2024_3245_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/c137569b461c/13046_2024_3245_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/51dd41671247/13046_2024_3245_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/fe0e17fadc14/13046_2024_3245_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/5a2e71582c37/13046_2024_3245_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/e0149b1948ce/13046_2024_3245_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/e3c44e4b7891/13046_2024_3245_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/c913e5a1d024/13046_2024_3245_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/c137569b461c/13046_2024_3245_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffeb/11657096/fe0e17fadc14/13046_2024_3245_Fig7_HTML.jpg

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