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溃疡性结肠炎组织图谱揭示了疾病驱动性炎症细胞类型存在性别依赖性差异及对 TNF 抑制剂治疗的抗性。

A tissue atlas of ulcerative colitis revealing evidence of sex-dependent differences in disease-driving inflammatory cell types and resistance to TNF inhibitor therapy.

机构信息

Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA.

Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.

出版信息

Sci Adv. 2023 Jan 20;9(3):eadd1166. doi: 10.1126/sciadv.add1166.


DOI:10.1126/sciadv.add1166
PMID:36662860
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9858501/
Abstract

Although literature suggests that resistance to TNF inhibitor (TNFi) therapy in patients with ulcerative colitis (UC) is partially linked to immune cell populations in the inflamed region, there is still substantial uncertainty underlying the relevant spatial context. Here, we used the highly multiplexed immunofluorescence imaging technology CODEX to create a publicly browsable tissue atlas of inflammation in 42 tissue regions from 29 patients with UC and 5 healthy individuals. We analyzed 52 biomarkers on 1,710,973 spatially resolved single cells to determine cell types, cell-cell contacts, and cellular neighborhoods. We observed that cellular functional states are associated with cellular neighborhoods. We further observed that a subset of inflammatory cell types and cellular neighborhoods are present in patients with UC with TNFi treatment, potentially indicating resistant niches. Last, we explored applying convolutional neural networks (CNNs) to our dataset with respect to patient clinical variables. We note concerns and offer guidelines for reporting CNN-based predictions in similar datasets.

摘要

虽然文献表明,溃疡性结肠炎(UC)患者对肿瘤坏死因子抑制剂(TNFi)治疗的耐药性部分与炎症区域的免疫细胞群有关,但相关的空间背景仍然存在很大的不确定性。在这里,我们使用高度多重免疫荧光成像技术 CODEX 对 29 名 UC 患者和 5 名健康个体的 42 个组织区域的 42 个组织进行了公共浏览的炎症组织图谱构建。我们分析了 1710973 个空间分辨的单细胞上的 52 个生物标志物,以确定细胞类型、细胞-细胞接触和细胞邻居。我们观察到细胞的功能状态与细胞邻居有关。我们进一步观察到,在接受 TNFi 治疗的 UC 患者中存在一部分炎症细胞类型和细胞邻居,这可能表明存在耐药性生态位。最后,我们探讨了在我们的数据集上应用卷积神经网络(CNN)的问题,以及与患者临床变量的关系。我们注意到报告基于 CNN 的预测的相关问题,并为类似数据集提供了指南。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cedc/9858501/e0cc2fcc52f9/sciadv.add1166-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cedc/9858501/3ceea2683f75/sciadv.add1166-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cedc/9858501/9b2ce9d61cc9/sciadv.add1166-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cedc/9858501/f239a56c2026/sciadv.add1166-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cedc/9858501/e0cc2fcc52f9/sciadv.add1166-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cedc/9858501/3ceea2683f75/sciadv.add1166-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cedc/9858501/9b2ce9d61cc9/sciadv.add1166-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cedc/9858501/f239a56c2026/sciadv.add1166-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cedc/9858501/e0cc2fcc52f9/sciadv.add1166-f4.jpg

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引用本文的文献

[1]
Unraveling the complexity of ulcerative colitis: insights into cytokine dysregulation and targeted therapies.

EXCLI J. 2025-6-6

[2]
Spatial Omics in Clinical Research: A Comprehensive Review of Technologies and Guidelines for Applications.

Int J Mol Sci. 2025-4-22

[3]
Relating the molecular phenotype of ulcerative colitis to the clinical course.

Sci Rep. 2025-3-11

[4]
Powerful and accurate case-control analysis of spatial molecular data with deep learning-defined tissue microniches.

bioRxiv. 2025-2-8

[5]
Spatial-Omics Methods and Applications.

Methods Mol Biol. 2025

[6]
Spatial profiling of the mouse colonic immune landscape associated with colitis and sex.

Commun Biol. 2024-11-29

[7]
A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease.

Nat Immunol. 2024-11

[8]
Answering open questions in biology using spatial genomics and structured methods.

BMC Bioinformatics. 2024-9-4

[9]
Safety and effectiveness of tofacitinib in Korean adult patients with ulcerative colitis: post-marketing surveillance study.

BMC Gastroenterol. 2024-8-19

[10]
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本文引用的文献

[1]
Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma.

Nat Commun. 2021-11-18

[2]
Highly Multiplexed Image Analysis of Intestinal Tissue Sections in Patients With Inflammatory Bowel Disease.

Gastroenterology. 2021-12

[3]
Coordinated Cellular Neighborhoods Orchestrate Antitumoral Immunity at the Colorectal Cancer Invasive Front.

Cell. 2020-10-29

[4]
Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses.

Sci Immunol. 2020-8-21

[5]
Sex-based differences in inflammatory bowel diseases: a review.

Therap Adv Gastroenterol. 2020-4-28

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Precision medicine in inflammatory bowel disease: concept, progress and challenges.

F1000Res. 2020-1-28

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The single-cell pathology landscape of breast cancer.

Nature. 2020-1-20

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AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis.

Gastroenterology. 2020-4

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Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study.

Lancet. 2020-1-11

[10]
Etiology and Management of Lack or Loss of Response to Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease.

Gastroenterol Hepatol (N Y). 2019-12

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