Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1
Callum Beach, … , Amato J. Giaccia, Monica M. Olcina
Callum Beach, … , Amato J. Giaccia, Monica M. Olcina
Published October 12, 2023
Citation Information: J Clin Invest. 2023;133(23):e168277. https://doi.org/10.1172/JCI168277.
View: Text | PDF | Corrigendum
Research Article Cell biology Oncology

Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1

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.

Authors

Callum Beach, David MacLean, Dominika Majorova, Stavros Melemenidis, Dhanya K. Nambiar, Ryan K. Kim, Gabriel N. Valbuena, Silvia Guglietta, Carsten Krieg, Mahnaz Darvish-Damavandi, Tatsuya Suwa, Alistair Easton, Lily V.S. Hillson, Ashley K. McCulloch, Ross K. McMahon, Kathryn Pennel, Joanne Edwards, Sean M. O’Cathail, Campbell S. Roxburgh, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Qingyang Zhang, 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

×

Figure 3

C5aR1 regulates tumor cell survival under stress.

Options: View larger image (or click on image) Download as PowerPoint
C5aR1 regulates tumor cell survival under stress. (A) HCT116 cells were ...
(A) HCT116 cells were treated with either vehicle or PMX205 (10 μg/mL) for 48 hours. Western blotting was carried with the antibodies indicated. (B) HCT116 cells were treated with 0 or 9 Gy and either vehicle or PMX205 for 1 hour before RT. Cells were harvested 48 hours after RT. Western blotting was carried with the antibodies indicated. (C) The ratio of dead (apoptotic) cells/nonapoptotic cells as a percentage of the whole population relative to vehicle-treated cells. n = 3. *P < 0.05, 2-tailed t test. (D) TUNEL+ cells per field of view of sections from HCT116 subcutaneous tumors. Mice were treated with 9 Gy and either vehicle or PMX205 (10 mg/kg) for 3 doses flanking RT. *P < 0.05, 2-tailed t test. (E) The number of dead(apoptotic)/nonapoptotic cells as a percentage of the whole population for HCT116 cells transfected with either Scr or IκBα siRNA and treated with either vehicle or PMX205 for 1 hour before RT. Cells were harvested 48 hours after RT. Independent fields of view from a representative experiment are shown, n = 3. *P < 0.05, 2-tailed t test. (F) Pearson’s correlation of mRNA expression of pro- and antiapoptotic genes with C5aR1 in TCGA samples from patients with CRC and rectal cancer biopsies from Grampian and Aristotle. *P < 0.05, ***P < 0.001, ****P < 0.0001. All TCGA data were accessed through cBioPortal (http://www.cbioportal.org/). All Grampian and Aristotle data were accessed through SCORT (stratification in colorectal cancer, http://www.cbioportal.org/). (G) Correlation of BCL2A1 and C5AR1 mRNA expression in TCGA CRC samples. (H) Correlation of BCL2A1 and C5AR1 mRNA expression in Grampian rectal cancer biopsies. (I) Correlation of BCL2A1 and C5AR1 mRNA expression in Aristotle rectal cancer biopsies. (J) Correlation of BCL2 and C5AR1 mRNA expression in TCGA CRC samples.