Targeting C5aR1 to improve radiation response of high-grade glioma

Thesis

High-grade gliomas (HGGs) are aggressive grade III or IV brain tumours originating from glial cells, characterised by rapid growth, poor prognosis and high recurrence rates. Radiotherapy remains the standard of care treatment for HGG, yet, treatment resistance, particularly due to its hypoxic nature, remains a key challenge, and a novel effective therapeutic strategy is needed to improve treatment efficacy. Despite the immunosuppressive tumour microenvironment, the complement receptor C5aR1 is overexpressed in glioblastoma and paediatric HGGs compared to healthy brain tissue. In this study, we identified that C5aR1 expression was upregulated under severe hypoxia in glioblastoma, driven by endoplasmic reticulum stress, and that C5aR1 signalling was critical for glioma cell survival. We also explored the potential of C5aR1 inhibition as a radiosensitising target in both glioblastoma and diffuse midline glioma, given its ability in modulating pro-survival signalling via G-protein coupled receptor activity. Both genetic silencing and pharmacological inhibition of C5aR1 enhanced glioma sensitivity to radiation and potentiated radiation-induced cytotoxicity. Importantly, these anti-survival effects were sustained under hypoxic conditions in 2D culture models, addressing a key barrier to radiotherapy efficacy. In contrast, C5aR1 inhibition in microglia did not reduce cell survival, but instead altered their inflammatory phenotype following irradiation. The suppression of microglia-derived pro-inflammatory factors, IL-1b in particular, was found to improve glioma radiosensitivity, highlighting a dual mechanism by which C5aR1 target may enhance radiation response and outcomes in HGGs.

Authors: Lee, SWK

• DOI: 10.5287/ora-e99dakx6a
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Radiation-sensitizing agents; Oncology