Beach, C. et al. (2023) Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1. Journal of Clinical Investigation, 133(23), e168277. (doi: 10.1172/JCI168277) (PMID:37824211) (PMCID:PMC10688992)
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Abstract
An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell–specific functions. C5aR1 targeting resulted in increased NF-κB–dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.
| Item Type: | Articles |
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| Additional Information: | This work was supported by MRC (MC_UU_00001/10), NIH Grants CA-67166 and CA-197713, the Silicon Valley Foundation, the Sydney Frank Foundation and the Kimmelman Fund (AJG). This work was also supported by Cancer Research UK (CR-UK) grant number C5255/A18085, through the Cancer Research UK Oxford Centre. MMO was a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute and Stiftung für Forschung, Medical Faculty, UZH. C.B is supported by an International Accelerator Award, ACRCelerate funded by Cancer Research UK (A26825 and A28223). RKK was supported by Stanford ChEM-H Undergraduate Scholars Program. MS and MMO were supported by a project grant from the Swiss National Foundation (31003A_163141). ED is supported by the S:CORT Consortium which is funded by a grant from the Medical Research Council and Cancer Research UK. TMW is supported by a fellowship from the National Health and Medical Research Council (2009957). |
| Keywords: | C5aR1, colorectal cancer, radiotherapy, complement. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Domingo, Dr Enric and Easton, Dr Alistair and Pennel, Miss Kathryn and Roxburgh, Professor Campbell and Edwards, Professor Joanne and McMahon, Mr Ross and Hillson, Lily and McCulloch, Mrs Ashley and O'Cathail, Dr Sean |
| Creator Roles: | Easton, A.Methodology, Writing – review and editing Domingo, E.Methodology, Writing – review and editing, Investigation, Formal analysis McCulloch, A.Investigation Hillson, L.Formal analysis McMahon, R.Formal analysis Pennel, K.Investigation Edwards, J.Supervision O'Cathail, S.Writing – review and editing, Supervision Roxburgh, C.Resources, Supervision |
| Authors: | Beach, C., MacLean, D., Majorova, D., Melemenidis, S., Nambiar, D. K., Kim, R. K., Valbuena, G. N., Guglietta, S., Krieg, C., Darvish, D. M., Suwa, T., Easton, A., Hillson, L. V.S., McCulloch, A. K., McMahon, R. K., Pennel, K., Edwards, J., O'Cathail, S. M., Roxburgh, C. S., Domingo, E., Moon, E. J., Jiang, D., Jiang, Y., Zhang, Q., Koong, A. C., Woodruff, T. M., Graves, E. E., Maughan, T., Buczacki, S. J.A., Stucki, M., Le, Q.-T., Leedham, S. J., Giaccia, A. J., and Olcina, M. M. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
| Journal Name: | Journal of Clinical Investigation |
| Publisher: | American Society for Clinical Investigation |
| ISSN: | 0021-9738 |
| ISSN (Online): | 1558-8238 |
| Copyright Holders: | Copyright: © 2023, Beach et al. |
| First Published: | First published in 133(23): e168277 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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