Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1
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
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
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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

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Figure 2

C5aR1 is a radiation-responsive druggable target.

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C5aR1 is a radiation-responsive druggable target. (A) Essential genes ar...
(A) Essential genes are shown in red. Nonessential genes are shown in green. Yellow/Orange indicates intermediate dependence or essentiality. For target tractability, green corresponds with druggable structure = Yes and druggable by ligand-based assessment = Yes. Red corresponds to druggable structure = No and druggable by ligand-based assessment = No. (B) Kaplan-Meier (KM) curve for disease-free survival (dfs) of TCGA patients with CRC with high (red) or low (blue) C4BPA mRNA expression. For all KM curves, group cutoff = median (http://gepia.cancer-pku.cn). (C) KM curve for dfs of TCGA patients with CRC with high (red) or low (blue) C5 mRNA expression. (D) KM curve for dfs of TCGA CRC with high (red) or low (blue) C5AR1 mRNA expression. (E) Quantification of C5aR1 immunohistochemistry staining in AKPT tumors. *P < 0.05, ordinary 1-way ANOVA, Dunnett’s multiple comparisons. All other comparisons relative to untreated were not significant. n = 5. (F) Representative images of multiplex and C5aR1 IHC staining in AKPT tumors (original magnification, ×40) Scale bar: 500 µm. (G) Proximity-based machine learning quantification of the percentage of C5aR1 staining in the epithelium and stroma of AKPT tumors. *P < 0.05, **P < 0.01, ****P < 0.0001, ordinary 1-way ANOVA with Tukey’s multiple comparisons. All other comparisons relative to untreated were not significant. n = 5. (H) Endoscopy images and representative examples of C5aR1 staining at baseline (W0) compared with W2 in longitudinal biopsies from patients with rectal adenocarcinoma. W2, week 2 after treatment. Numbers refer to patient number, week after treatment, or TNM stage. Scale bar: 100 mm. (I) H-Scores of C5aR1 staining in epithelial and stromal areas of cancerous tissue from rectal adenocarcinoma longitudinal biopsies taken at W0 compared with W2. (J) mRNA expression of C5AR1/housekeeping in HCT116 cells treated with either 0 or 9 Gy. n = 3. **P < 0.01, 2-tailed t test. (K) mRNA expression of C5/housekeeping in HCT116 cells treated as in J. n = 3. Two-tailed t test. (L) C5aR1 median fluorescence intensity in HCT116 cells treated with either 0 or 9 Gy. n = 3. *P < 0.05, 2-tailed t test.