This technology provides methods and compositions that use GPR183 expression in B cells and regulatory T cells (Tregs) to predict, prevent, and treat immune-related adverse events (irAEs) associated with cancer immunotherapy, while also enhancing anti-tumor immunity. By measuring and modulating GPR183-driven immune cell positioning in distinct immune compartments, this approach offers a path to uncouple the toxicity of checkpoint blockade therapy from its therapeutic benefit.
Description
Immune checkpoint blockade therapies can produce durable anti-tumor responses, but their clinical use is frequently limited by irAEs, and current management relies on broad immunosuppression that can compromise anti-tumor immunity. This technology is based on the discovery that GPR183, a G protein-coupled receptor that responds to oxysterol ligands, marks and regulates a disease-relevant immune cell positioning program in two distinct compartments: B cells associated with irAEs, and Tregs associated with tumor immune suppression.
The core methods involve determining GPR183 expression levels in a biological sample to identify patients at increased risk of developing irAEs (when GPR183 is elevated in B cells) or patients whose tumors are enriched for an immunosuppressive Treg program (when GPR183 is elevated in tumor-associated Tregs). These biomarker readouts can then inform treatment decisions, including selecting patients for combination therapy with a GPR183 modulator alongside an anti-cancer treatment such as an immune checkpoint inhibitor.
Applications
- Companion diagnostic assays to predict irAE risk prior to or during immune checkpoint blockade therapy
- Biomarker-based patient stratification tools to identify tumors enriched for immunosuppressive Treg programs
- Combination therapeutics pairing GPR183 modulators with immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4) to improve efficacy while reducing toxicity
- Diagnostic kits (antibody- or primer-based) for monitoring GPR183 expression in clinical or research settings
- Novel immuno-oncology therapeutics targeting GPR183 signaling as a monotherapy or adjunct to existing cancer treatments
Advantages
- Enables prediction of immune-related adverse event risk before or during immunotherapy, supporting proactive clinical management
- Distinguishes toxicity-associated immune positioning (B cells) from tumor-associated immunosuppressive positioning (Tregs), allowing compartment-specific intervention
- Offers a strategy to reduce immune-mediated toxicity without broadly suppressing anti-tumor immune activity
- Compatible with multiple modulator formats (small molecules, antibodies, nucleic acid-based agents), providing flexibility in therapeutic design
- Applicable across a broad range of solid and hematological cancers and multiple immunotherapy modalities
Invention Readiness
The technology is currently supported by preclinical data generated using a murine model designed to induce susceptibility to immune-related adverse events through diet-induced metabolic and microbiome perturbations, combined with anti-PD-1 checkpoint blockade. In these studies, GPR183 expression was linked to B-cell redistribution into inflamed tissues and to Treg-mediated immunosuppression in tumors, and pharmacological inhibition of GPR183 using a research-grade antagonist improved anti-tumor responses while reducing inflammatory toxicity. Correlative analyses of human immune profiling datasets provided additional support for the association between GPR183 expression and clinical outcomes. Further studies are needed to validate these findings in additional preclinical models, optimize and characterize additional GPR183 modulators for therapeutic use, and translate the diagnostic and therapeutic approach into human clinical studies.
IP Status
Patent Pending
