Biology subjects

Buczacki, S. J.

Publications and source records attributed to Buczacki, S. J..

2 recordsLinked to original sources

bioRxiv2025

Targeting C5aR1 Reveals Protective Macrophage Maturation States in Intestinal Injury

Inflammatory intestinal injury, which may occur following cytotoxic cancer treatments such as radiotherapy, compromises homeostasis when intestinal stem cells undergo apoptosis and regeneration programmes are not effectively engaged. Recent evidence indicates the importance of macrophages in regulating stem regeneration following injury, but how to therapeutically promote specific macrophage subtypes which may tip the balance away from apoptosis and towards regeneration is still unclear. Here we show that targeting complement C5a receptor 1 (C5aR1) reduces radiation-induced intestinal injury by promoting macrophage phenotypes which reduce intestinal stem cell apoptosis. Specifically, C5aR1 signalling attenuates a macrophage maturation response characterised by increased IL10 and CX3CR1 expression. Our data indicate that increased IL10 signalling, and macrophage maturation induced following C5aR1 targeting are important for regulating crypt cell loss via radiotherapy-induced apoptosis. Interestingly, IL10-signalling is also critical for the improved tumour radiation response observed following C5aR1 targeting.

immunology↗

bioRxiv2023

Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments

An immunosuppressive microenvironment causes poor tumour T-cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumours is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identify complement receptor C5aR1 as a druggable target which when inhibited improves radiotherapy even in tumours displaying immunosuppressive features and poor CD8+ T-cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we find that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumour-cell specific functions. C5aR1 targeting results in increased NF-{kappa}B-dependent apoptosis specifically in tumours and not normal tissues; indicating that in malignant cells, C5aR1 primarily regulates cell fate. Collectively, these data reveal that increased complement gene expression is part of the stress response mounted by irradiated tumours and that targeting C5aR1 can improve radiotherapy even in tumours displaying immunosuppressive features.

cancer biology↗