Dataset Information

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.

SUBMITTER: Beach C

PROVIDER: S-EPMC10688992 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

Beach Callum C MacLean David D Majorova Dominika D Melemenidis Stavros S Nambiar Dhanya K DK Kim Ryan K RK Valbuena Gabriel N GN Guglietta Silvia S Krieg Carsten C Darvish-Damavandi Mahnaz M Suwa Tatsuya T Easton Alistair A Hillson Lily Vs LV McCulloch Ashley K AK McMahon Ross K RK Pennel Kathryn K Edwards Joanne J O'Cathail Sean M SM Roxburgh Campbell S CS Domingo Enric E Moon Eui Jung EJ Jiang Dadi D Jiang Yanyan Y Zhang Qingyang Q Koong Albert C AC Woodruff Trent M TM Graves Edward E EE Maughan Tim T Buczacki Simon Ja SJ Stucki Manuel M Le Quynh-Thu QT Leedham Simon J SJ Giaccia Amato J AJ Olcina Monica M MM

The Journal of clinical investigation 20231201 23

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 infiltra ...[more]

PMID: 37824211

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Project description:The contribution of the gut microbiome to neuroinflammation, cognition, and Alzheimer's disease progression has been highlighted over the past few years. Additionally, inhibition of various components of the complement system has repeatedly been demonstrated to reduce neuroinflammation and improve cognitive performance in AD mouse models. Whether the deletion of these complement components is associated with distinct microbiome composition, which could impact neuroinflammation and cognitive performance in mouse models has not yet been examined. Here, we provide a comprehensive analysis of conditional and constitutive knockouts, pharmacological inhibitors, and various housing paradigms for the animal models and wild-type controls at various ages. We aimed to determine the impact of C1q or C5aR1 inhibition on the microbiome in the Arctic and Tg2576 mouse models of AD, which develop amyloid plaques at different ages and locations. Analysis of fecal samples from WT and Arctic mice following global deletion of C1q demonstrated significant alterations to the microbiomes of Arctic but not WT mice, with substantial differences in abundances of Erysipelotrichales, Clostridiales and Alistipes. While no differences in microbiome diversity were detected between cohoused wildtype and Arctic mice with or without the constitutive deletion of the downstream complement receptor, C5aR1, a difference was detected between the C5aR1 sufficient (WT and Arctic) and deficient (C5ar1KO and ArcticC5aR1KO) mice, when the mice were housed segregated by C5aR1 genotype. However, cohousing of C5aR1 sufficient and deficient wildtype and Arctic mice resulted in a convergence of the microbiomes and equalized abundances of each identified order and genus across all genotypes. Similarly, pharmacologic treatment with the C5aR1 antagonist, PMX205, beginning at the onset of beta-amyloid plaque deposition in the Arctic and Tg2576 mice, demonstrated no impact of C5aR1 inhibition on the microbiome. This study demonstrates the importance of C1q in microbiota homeostasis in neurodegenerative disease. In addition, while demonstrating that constitutive deletion of C5aR1 can significantly alter the composition of the fecal microbiome, these differences are not present when C5aR1-deficient mice are cohoused with C5aR1-sufficient animals with or without the AD phenotype and suggests limited if any contribution of the microbiome to the previously observed prevention of cognitive and neuronal loss in the C5aR1-deficient AD models.

Dataset Information

Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

Publications

Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

Similar Datasets

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