Immune Landscape of early liver metastatic lesions in a Novel Immunocompetent Murine Colorectal Cancer Metastasis Model

<p>Colorectal cancer minimal residual disease (MRD) represents a major clinical problem for colorectal cancer patients, with failure rates of surgery and adjuvant chemotherapy between 5% to 40% depending on stage of disease. In our study, we simulated MRD using genetically engineered organoids with precise somatic editing of APC and TP53, creating a murine model that mimics human liver metastatic colorectal cancer. By implementing a meticulously timed experimental metastatic model, we could detect microscopic tumor lesions. Through genomic and transcriptomic analyses, we pinpointed the importance of macrophages, particularly those expressing high levels of CSF1R, in these microscopic metastatic focal lesions. We conducted macrophage- targeted immunotherapy using anti-CSF1R. Treatment of micro-metastases resulted in complete remission of microscopic disease and eradication of macrophages expressing CD163+ after four weeks of treatment. However, anti-CSF1R treatment did not exhibit efficacy in treating macro-metastases. Spatial transcriptomic analysis, along with multiplex immunofluorescent analysis, demonstrated the effectiveness of anti-CSF1R treatment in significantly reducing macrophage populations and enhancing CD8+ T cells after 14 days of treatment. Anti-CSF1R holds promise as a targeted therapy for colorectal cancer MRD patients.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Author dc:creator

• Mohamed, Alaa

Contributors dc:contributor

• Scott Kopetz
• Giulio Draetta
• David Menter

• Colorectal cancer
• Tumor immune microenvironment
• Immunology
• Genetics
• Immunotherapy
• Genetic engineering mouse models
• Medical Genetics
• Medical Immunology
• Oncology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1414

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2471