Understanding the role of innate immunity in treatment-induced normal tissue injury
Second Supervisor: Prof Simon Buczacki
Achieving the right balance between appropriate tumour control and limited toxicity to healthy tissues is important for cancer treatment. Further improvements in our understanding of the mechanisms underlying treatment-induced normal tissue injury could lead to the identification of therapeutic targets that reduce normal tissue toxicity while simultaneously improving tumour response. We are interested in investigating druggable innate immunity proteins that, when targeted, simultaneously improve tumour response and reduce normal tissue toxicity. Our previous work has identified complement receptor, C5aR1 as a key modulator of both tumour response and radiation-induced bowel toxicity. 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. We identify that C5aR1 primarily regulates cell fate in malignant cells, and that C5aR1 targeting results in increased NF-B-dependent apoptosis specifically in tumours and not normal tissues. Crucially, targeting C5aR1 improves tumour response while reducing normal tissue toxicity following irradiation in the abdominal cavity. The aim of this project is to investigate the role of C5aR1 in modulating recovery from injury, including the mechanisms underlying the intriguing opposite effect of C5a/C5aR1 signalling in regulating cell fate in transformed and untransformed cells. The role of C5aR1 within the inflammatory milieu, and how this might impact normal tissue recovery will also be investigated. Understanding how C5aR1 signalling regulates intestinal injury will help us understand how to apply future C5a/C5aR1 targeting therapies to reduce treatment-related side effects.
By undertaking this project the student will benefit from working in two laboratories with complementary expertise in innate immunity, radiobiology (Olcina) and intestinal stem cell biology (Buczacki). Furthermore, the student will have the opportunity to develop expertise in a range of laboratory techniques including how to work with organoid cultures, flow cytometry, immunohistochemistry and standard cell and molecular biology techniques. The student will likely also acquire experience in using colorectal cancer models with clinically relevant molecular phenotypes while working both independently as well as in a team. Career development opportunities will be offered, including attendance of national and international conferences and transferable skills training courses.
Beach, C., MacLean, D., Majorova, D., Melemenidis, S., Nambiar, D.K., Kim, R.K., Valbuena, G.N., Guglietta, S., Krieg, C., Damavandi, M.D. and Suwa, T., 2023. Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments. bioRxiv, pp.2023-01.
Olcina, M.M., Stavros, M., Nambiar, D.K., Kim, R.K., Casey, K.M., Rie, V.E., Woodruff, T.M., Graves, E.G., Quynh-Thu, L., Manuel, S. and Giaccia, A.J., 2020. Targeting C5aR1 increases the therapeutic window of radiotherapy. bioRxiv, pp.2020-10.