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.
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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 4

C5aR1 deficiency does not result in increased apoptosis in healthy intestinal epithelium.

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C5aR1 deficiency does not result in increased apoptosis in healthy intes...
(A) Heatmap of complement genes differentially expressed by RNA-Seq in WT, AKPT, or KPN organoids grown in vitro. Upregulation is shown in red, as per Z-score indicated below. Data for 3 independent samples is shown from data deposited at the ArrayExpress database under accession number E-MTAB-11769 (46). (B) C5aR1 expression (CPM) assessed by RNA-Seq in WT, AKPT, or KPN organoids grown in vitro as in A. ***P < 0.001, empirical Bayes moderated t-statistic test. (C) mRNA expression of Bcl2, Bcl2l1, Bcl2l2, Ier3, and Xiap in WT or C5aR1–/– mice treated with 9 Gy. Points indicate individual mice per group. n = 3. *P = 0.0468, unpaired 2-tailed t test. (D) The average TUNEL+ cells/crypt of BALBc/J mice treated with either 0 or 9 Gy and either vehicle or PMX205. Intestines were harvested 72 hours after RT. n = 4/5 mice per group. ****P < 0.0001, by ordinary 1-way ANOVA with Tukey’s multiple comparisons. (E) The average TUNEL+ cells/crypt of C57BL/6 mice treated with 9 Gy and either vehicle or PMX205. Intestines were harvested 72 hours after RT. n = 3 mice per group. **P < 0.01, 2-tailed t test. (F) The average number of TUNEL+ cells of WT or C5aR1–/– mice treated with 9 Gy. Intestines were harvested 48 hours after RT. n = 3 mice per group. *P < 0.05, 2-tailed t test.