T-cell responses in colorectal peritoneal metastases are recapitulated in a humanized immune system mouse model

Job Saris ^1,2,3,4,5, Sanne Bootsma ^2,3,5,6, Jan Verhoeff ^2,3,4,5,7,8

¹Department of Gastroenterology and Hepatology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands.
²Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands.
³Cancer Center Amsterdam, Amsterdam, Netherlands.
⁴Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands.
⁵Oncode Institute, Amsterdam, Netherlands.
⁶Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands.
⁷Molecular Cell Biology & Immunology, Amsterdam UMC location Vrije Universiteit, Amsterdam, Netherlands.
⁸Amsterdam Infection & Immunity Institute, Amsterdam, Netherlands.
⁹Department of Surgery, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
¹⁰HIS Mouse Facility, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands.

⁰Department of Gastroenterology and Hepatology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands.

Frontiers in Immunology +

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July 24, 2024

View abstract on PubMed

Summary

A new humanized immune system (HIS) mouse model accurately mimics colorectal cancer (CRC) peritoneal metastasis (PM) in patients. This model is valuable for studying anti-tumor T cell responses in peritoneal metastasis.

Area Of Science

Immunology
Oncology
Translational Medicine

Background

Peritoneal metastasis (PM) in colorectal cancer (CRC) presents a poor prognosis with limited treatment efficacy.
Understanding the peritoneal immune microenvironment is crucial for overcoming therapy resistance in PM-CRC.
Developing robust preclinical models is essential for studying anti-tumor immune responses in PM-CRC.

Purpose Of The Study

To define the peritoneal immune system (PerIS) in PM-CRC patients.
To evaluate a humanized immune system (HIS) mouse model for its preclinical potential in studying PM-CRC.
To compare immune cell populations and responses between human PM-CRC and the HIS mouse model.

Main Methods

Analysis of PerIS in PM-CRC patients (n=20) and healthy controls (n=3) using CyTOF.
Generation of HIS mice (NODscid gamma background; n=18).
Intraperitoneal injection of CRC cell lines into HIS mice to establish a PM-CRC model, followed by CyTOF analysis of immune cells.

Main Results

The HIS mouse model and human PerIS showed similarities in NK, CD4+, and CD8+ T cell populations, with observed differences in macrophages and B cells.
Successful engraftment of both microsatellite stable (MSS) and microsatellite unstable (MSI) CRC tumors was achieved in 100% of HIS mice.
MSS PM-CRC induced a CD4+ regulatory T cell (Treg) response, while MSI PM-CRC stimulated CD8+ effector memory T cell (TEM) responses in both human patients and the HIS mouse model.

Conclusions

The HIS mouse model effectively replicates human T cell responses observed in PM-CRC.
This HIS mouse model is a suitable preclinical tool for investigating anti-tumor T cell responses in the context of PM-CRC.
Findings highlight distinct immune responses based on microsatellite stability in PM-CRC, informing future therapeutic strategies.

Keywords:

CyTOF T-cell biology colorectal cancer humanized immune system peritoneal immune system peritoneal metastasis

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