Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments
Year: 2023
Type: preprint
Abstract: 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-κB-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.
Authors: Callum Beach, David MacLean, Dominika Majorova, Stavros Melemenidis, Dhanya K. Nambiar, Ryan K. Kim, Gabriel N Valbuena, Silvia Guglietta, Carsten Krieg, Damavandi Mahnaz Darvish, Tatsuya Suwa, Alistair Easton, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Albert C Koong, Trent M. Woodruff, Edward E. Graves, Tim Maughan, Simon J. A. Buczacki, Manuel Stucki, Quynh-Thu Le, Simon J. Leedham, Amato J. Giaccia, Monica M Olcina
Institutions: University of Oxford, CRUK/MRC Oxford Institute for Radiation Oncology, Stanford University, Centre for Human Genetics, Medical University of South Carolina, MUSC Hollings Cancer Center, The University of Texas MD Anderson Cancer Center, The University of Queensland, University of Zurich
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1271970818, G1325498775, Targeting the complement system to improve radiation response, G2555714370, G3994082246, G4643374311, G4741391056, G5118354679, G5718954505, G6987710327, Developing new therapies targeting innate immune mediated inflammation in neurodegenerative disease, G9000069745, G9000098391
OpenAlex ID: W4315465091