Immune Landscape of Minimal Residual Disease in a Novel Immunocompetent Murine Colorectal Cancer Metastasis Model

Advisor: Scott Kopetz, MD, PhD; Secondary Advisor: Giulio Draetta, MD)

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.  There is a critical need to understand and model this minimal residual disease state. In this study, we modeled MRD using genetically engineered organoids with targeted somatic editing of APC and TP53, generating a preclinical murine model recapitulating human liver metastatic colorectal cancer. We implemented a precise timeline to our experimental metastatic model through which we are able to detect microscopic tumor lesions. Through genomic and transcriptomic profiling, we identified the significance of macrophages and specifically macrophages highly expressing CSF1R in those microscopic metastatic focal lesions. We performed macrophage targeted immunotherapy using anti-CSF1R, the treatment of micro-metastases showed complete remission of microscopic disease with eradication of macrophages expressing CD163+ after four weeks of treatment, while lack of efficacy of anti-CSF1R treatment in macro-metastases treatment. Spatial transcriptomic analysis as well as multiplex immunofluorescent analysis showed the efficacy of anti-CSF1R treatment in the significant depletion of macrophages and the enhancement of CD8+ T cells after 14 days of treatment.  Anti-CSF1R could be a promising targeted therapy for colorectal cancer MRD patients.

Advisory Committee:
Scott Kopetz, MD, PhD, Chair
Giulio Draetta, MD
Michelle Barton, PhD
Kristin Eckel-Mahan, PhD
Giannicola Genovese, MD, PhD
Anirban Maitra, MBBS
David Menter, PhD