CCR9 shapes the immune microenvironment of colorectal cancer - Modulating the balance between intratumoral CD8+ T cell and FoxP3+ Helios+ Treg subpopulations

Sep 23, 2026

Uploaded by James

Colorectal cancer (CRC) is a leading cause of cancer mortality, and regulatory T cell (Treg) infiltration is linked to suppression of anti-tumor immunity. In the gut, Helios+ thymic Tregs and Helios− peripheral Tregs coexist to maintain homeostasis, while recruitment is driven by the CCR9/CCL25 axis and intensified during inflammation. This study tests whether CCR9 regulates the intratumoral CD8+/Treg balance and the recruitment of Treg subpopulations using an AOM/DSS colitis-associated CRC murine model. CCR9 deficiency decreases intratumoral Helios+ Tregs and increases the CD8+/Treg ratio, improving antitumor immune responses and highlighting CCR9’s role in CRC immune microenvironment shaping.

LanguageEnglish

CategoryHealthcare

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Pages16

Reading Time40 min

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OPEN ACCESS Citation: Martínez-Ríos J, López-Pacheco CP, García-Zepeda EA, Soldevila G (2025) ssCCR9 shapes the immune microenvironment of colorectal cancer modulating the balance between intratumoral CD8+ T cell and FoxP3+ Helios+ Treg subpopulations. PLoS One 20(4): e0321930. [https://doi.org/10.1371/journal](https://doi.org/10.1371/journal). pone.0321930 Editor: Xiaonan Han, Cincinnati Children's Hospital Medical Center, UNITED STATES OF AMERICA Received: October 7, 2024 Accepted: March 12, 2025 Published: April 30, 2025 Copyright: © 2025 Martínez-Ríos et al. This isan open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data availability statement: “All relevant data are within the paper and its Supporting Information files.” RESEARCH ARTICLE CCR9 shapes the immune microenvironment of colorectal cancer modulating the balance between intratumoral CD8+ T cell and FoxP3+ Helios+ Treg subpopulations Jacobo Martínez-Ríos1, Cynthia Paola López-Pacheco1,2, Eduardo Alberto García-Zepeda1, Gloria Soldevila1,3* 1 Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico, 2 Investigadora por México, Secretaría de Ciencia Tecnologíay Humanidades (SECIHTI), Mexico City, Mexico, 3 Laboratorio Nacional de Citometría de Flujo, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico * [soldevi@iibiomedicas.unam.mx](soldevi@iibiomedicas.unam.mx) Abstract Colorectal cancer (CRC) is the third most common cancer in the world and the second cause of death related to cancer. Regulatory T cell (Treg) infiltration is enriched in several tumor types including CRC and correlates with suppression of the anti-tumor immune response. In the large intestine, thymic Tregs (tTregs Helios+) and peripheral Tregs (pTregs Helios − ) coexist and maintain intestinal homeostasis under steady state conditions. The recruitment of Treg cells to the intestine is orchestrated by the CCR9/CCL25 axis, which is potentiated under inflammatory conditions. Interestingly, the balance between cytotoxic CD8+ T cells and Tregs within the tumor microenvironment is critical for antitumor immunity and cancer progression. An elevated CD8+/Treg ratio has been associated with improved clinical outcomesin various cancers, including CRC. Therefore, here we investigate the potential role of chemokine receptor CCR9 on CD8+/Treg ratio and the effect of the recruitment of Treg subpopulations (Helios+ and Helios − ) into the tumor microenvironment using the AOM/DSS induced colitis-associated colorectal cancer murine model. Our findings reveal that CCR9 deficiency leads to distinct alterations in the CRC microenvironment, characterized by decreased intratumoral Tregs Helios+ . Also, the lack of the receptor leads to an improvement of the antitumor immune response, increasing the CD8+/Treg ratio within the tumor immune infiltrate. These results underscore the importance of CCR9 in shaping the immune microenvironment during CRC development. PLOS One | [https://doi.org/10.1371/journal.pone.0321930](https://doi.org/10.1371/journal.pone.0321930) April 30, 2025 1 / 16 Funding: The work was supported by Consejo Nacional de Ciencia y Tecnología, Grant no. 167913. JMR was supported by a predoctoral fellowship from Conahcyt (262873) . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Introduction Colorectal cancer (CRC) is the leading cause of cancer-related deaths among men and women in developing countries [ 1] . Several risk factors, such as diet, genetic predisposition and chronic inflammation have been strongly lin

FAQs

What role does Treg infiltration play in colorectal cancer?

Treg infiltration is enriched in CRC and correlates with suppression of the anti-tumor immune response.

How is CCR9 linked to intestinal Treg recruitment?

Treg recruitment to the intestine is orchestrated by the CCR9/CCL25 axis, which is potentiated under inflammatory conditions.

What did the study find when CCR9 was deficient?

CCR9 deficiency caused distinct alterations in the CRC microenvironment, including decreased intratumoral Helios+ Tregs and an increased CD8+/Treg ratio that supports an improved antitumor immune response.

Sep 23, 2026

Uploaded by James