Single-cell transcriptomics reveals antigen-presenting capacity and therapeutic resistance potential of immunomodulatory endothelial cells in colorectal cancer - Original research article

Sep 21, 2026

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Single-cell transcriptomics dissects heterogeneity in tumor endothelial cells and addresses why antiangiogenic therapies often fail. Immunomodulatory endothelial cells (IMECs), a functional EC subgroup, are evaluated for their ability to shape tumor immune balance and affect existing AATs. Integrated analyses of colorectal cancer single-cell transcriptomes assess EC subset gene signatures, cellular composition differences, and cell–cell interactions with CD4+ T cells. Results indicate IMECs can present MHC-II antigens to mature CD4+ T cells, with subset-specific angiogenesis changes and potential reduced AAT efficacy via therapeutic resistance mechanisms.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Abstract

Introduction

Tumor endothelial cell heterogeneity and antiangiogenic therapy limitations

Definition and rationale for immunomodulatory endothelial cells (IMECs)

Methods

Data integration from colorectal cancer single-cell RNA-seq datasets

Analysis of gene signatures, cellular composition, and cell–cell interactions

Results

IMEC subsets and MHC-II antigen presentation to CD4+ T cells

Subset-specific CD4+ T cell interactions and angiogenesis-related gene expression

Impact of immunotherapy on angiogenesis scores and AAT resistance potential

Conclusion

DOI: 10.1002/iid3.1311 ORIGINAL ARTICLE Single‐cell transcriptomics reveals antigen‐presenting capacity and therapeutic resistance potential of immunomodulatory endothelial cells in colorectal cancer Jingyi Wen School of Biology and Biological Engineering, South China University of Technology, Guangzhou, Guangdong, China Correspondence Jingyi Wen, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, Guangdong, China. [Email:](Email: wenjingyi_1@outlook.com)[ wenjingyi_1@outlook.com](Email: wenjingyi_1@outlook.com) Abstract Background: The heterogeneity of tumor endothelial cells (TECs) hinders the efficacy of antiangiogenic therapies (AATs) . Only a small percentage ofangiogenic TECs are considered effective targets for AATs. Immunomodulatory ECs (IMECs), as a newly focused functional subgroup of endothelial cells (ECs), are being evaluated for their ability to regulate tumor immune balance and influence existing AATs. Methods: Based on single‐cell transcriptome data from colorectal cancer in a publicly available database, we conducted a wide array of bioinformatic approaches to study EC subsets that meet the IMECs definition. Our investigation encompassed the gene expression signatures of these subsets, cellular composition differences, cell–cell interactions. Results: Two subsets that meet the IMECs definition were found in tumorsand para‐cancerous tissues. Combined with the results of gene ontological analysis and interaction with CD4+ T cells, we found that IMECs can present MHC‐II antigens to mature CD4+ T cells. There were differences in the level of interaction between IMECs and different types of mature CD4+ T cell subsets. In addition, IMEC subsets had different expression levels of angiogenesis related genes. The angiogenesis score of IMECs decreased after patients received immunotherapy. IMEC subsets do not depend on a single proangiogenic receptor and are involved in regulating angiogenesis, which may reduce the efficacy of AATs. The adverse effects of specific IMEC subsetson AATs were validated in the RNA‐seq dataset of the bevacizumab treatment group. Conclusion: Our study suggests the potential MHC‐II antigen presentation capacity of IMECs and the enhanced angiogenesis characteristics within tumors. The function of IMECs in the vascular network may have a potentially adverse effect on AATs. Controlling the functional properties of IMECs may bea new angle for tumor therapy. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2024 The Author(s) . Immunity, Inflammation and Disease published by John Wiley & Sons Ltd. Immun Inflamm Dis. 2024;12:e1311 . [https://doi.org/10.1002/iid3.1311](https://doi.org/10.1002/iid3.1311) [wileyonlinelibrary.com/journal/iid3](wileyonlinelibrary.com/journal/iid3) 1 of 19 KEYW OR DS angiogenesis, antiangiogenic therapies, antigen presentation, colorectal cancer, immunomodulatory, tumor endothelial cells 1 | INTRODUCTION In addition to building a functional vascular network,1 vascular endothelial cells (vECs) also play special roles in immune regulation, including immune cell recruitment and antigen presentation.2 Based on the involvement of vECs in abnormal angiogenesis within tumors, antiangiogenic therapies (AATs) have been introduced into tumor therapy and has been shown to delay tumor progression in a variety of cancer therapies.3 However, AATs are less effective than expected, including drug resistance3 and limitations in cancer types.4,5 For colorectal cancer (CRC), AATs do not provide clinical benefits for adjuvant treatment of CRC compared with metastatic CRC.6 One possible reason is that the phenotype and function of tumor endothelial cells (TECs) are heterogeneous,7 providing TECs with a potential escape mechanism for AATs. Through single‐cel

FAQs

What motivated the study of immunomodulatory endothelial cells in colorectal cancer?

Tumor endothelial cell heterogeneity limits the efficacy of antiangiogenic therapies. The study focuses on IMECs as a subgroup that may regulate tumor immune balance and influence treatment response.

How were IMECs analyzed in this research?

The study integrated single-cell transcriptome data from colorectal cancer and applied bioinformatic analyses to identify EC subsets matching IMEC definitions, including gene expression signatures, cellular composition, and cell–cell interactions.

What key immune-related function of IMECs was reported?

IMECs can present MHC-II antigens to mature CD4+ T cells, and the strength of interaction varies across different mature CD4+ T cell subsets.

How might IMECs contribute to therapeutic resistance against antiangiogenic therapies?

IMEC subsets show decreased angiogenesis scores after immunotherapy and differ in expression of angiogenesis-related genes. The study suggests IMEC angiogenesis regulation may reduce AAT efficacy, supported by validation in a bevacizumab RNA-seq dataset.

Sep 21, 2026

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