Understanding complement system dysregulation in the tumour microenvironment
About the research:
Inducing a stress response analogous to anti-viral immunity is important for maximising immune responses against the tumour. However, tumours evolve evasion strategies that can limit these responses. Our previous work has demonstrated that there are strong selection pressures to dysregulate the complement system in the tumour microenvironment (TME). Complement dysregulation can favour both cancer cell survival and immune evasion strategies, however, the mechanisms underlying these effects are not well understood. We hypothesise that immune evasion could be mediated via increased transcriptional expression of negative complement regulator CD55 in poorly oxygenated (hypoxic) areas of the tumour. We think that in hypoxic tumours high levels of CD55 expression prevent complement-mediated cytotoxicity of tumour cells while favouring the tumour promoting properties of complement. In line with this notion, colorectal cancer tumours displaying poor outcomes have high expression of a range of effector complement proteins. However, we currently don’t understand how expression of these proteins is regulated in the TME and what the consequences of such high expression are for tumour progression and treatment failure. This project will investigate the molecular mechanisms underlying dysregulation of complement proteins in tumour cells and how such dysregulation impacts tumour cell survival and immune evasion. Molecular mechanisms will be dissected using genetic manipulation in cell lines and organoids (e.g. using CRISPR-Cas9 systems). The impact of complement dysregulation on spatial localisation and relative abundance of innate and adaptive immune cells in the TME will be assessed using multiplex image analysis platforms such as HALOÒ. These studies will be carried out in mouse and human tumour and normal tissue samples. This project will help us understand how best to modulate innate immune responses to improve radiation and immunotherapy responses.
Our group works in a collaborative and multidisciplinary manner. We are interested in a basic to translational approach to science, so we collaborate with clinicians and use patient samples or clinical data whenever possible. We also have experience working with in a range of model systems - from cell lines to in vivo mouse models. Students can also expect to receive training in bioinformatics and cell and molecular biology techniques such as western blotting, qPCR and confocal microscopy. Students will have the opportunity to attend one national and one international conference throughout their DPhil. All members of the lab attend weekly lab meetings which include data presentations, troubleshooting and journal clubs. Dr Olcina meets with students in one-to-one meetings at least once every two weeks.
Olcina MM, Balanis NG, Kim RK, Aksoy BA, Kodysh J, Thompson MJ, Hammerbacher J, Graeber TG, Giaccia AJ. Cell Reports. 2018 Dec 26.
The tumour microenvironment links complement system dysregulation and hypoxic signalling. Olcina MM, Kim, RK, Melemenidis, S. Graves EE, Giaccia, AJ. Br J Radiol. 2019 Jan.
Olcina MM, Kim RK, Balanis NG, Li Caiyun G, von Eyben R, Graeber TG, Ricklin D, Stucki M and Giaccia AJ. iScience. 2020 Sept 21.