Synthetic GPR84 Agonists in Colorectal Cancer: Effective in THP-1 Cells but Ineffective in BMDMs and MC38 Mouse Tumor
Marlene Schwarzfischer1, Maria Rae Walker1, Michele Curcio2,3
1Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, 8091 Zürich, Switzerland.
Abstract:
Tumor-associated macrophages (TAMs) in the colorectal cancer (CRC) microenvironment promote tumor progression but can be reprogrammed into a pro-inflammatory state with anti-cancer properties. Activation of the G protein-coupled receptor 84 (GPR84) is associated with pro-inflammatory macrophage polarization, making it a potential target for CRC therapy. This study evaluates the effects of the GPR84 agonists 6-OAU and ZQ-16 on macrophage activation and anti-cancer efficacy. GPR84 expression on THP-1 macrophages and murine BMDMs was analyzed using flow cytometry. Macrophages were treated with 6-OAU or ZQ-16, and pro-inflammatory cytokine levels, reactive oxygen species (ROS) production, and phagocytosis were assessed using qPCR and functional assays. Anti-cancer effects were tested in a subcutaneous MC38 tumor model, with oral or intraperitoneal agonist administration. Pharmacokinetics and compound stability were also evaluated. In THP-1 macrophages, 6-OAU increased pro-inflammatory cytokines and ROS production, with ZQ-16 showing similar effects. However, neither agonist induced pro-inflammatory responses, ROS production, or phagocytosis in murine macrophages. In vivo, both agonists failed to inhibit tumor growth in the MC38 model despite systemic exposure. Current GPR84 agonists lack efficacy in promoting anti-cancer macrophage activity, limiting their potential as CRC therapies.
Insights
GPR84 agonists showed no anti-cancer effects in colorectal cancer models. Current agonists failed to activate macrophages or inhibit tumor growth, limiting their therapeutic potential.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Tumor-associated macrophages (TAMs) in colorectal cancer (CRC) promote tumor growth.
- Reprogramming TAMs to an anti-cancer state is a therapeutic strategy.
- G protein-coupled receptor 84 (GPR84) activation is linked to pro-inflammatory macrophage polarization.
Purpose of the Study:
- To evaluate the anti-cancer efficacy of GPR84 agonists 6-OAU and ZQ-16.
- To assess the impact of these agonists on macrophage activation and colorectal cancer progression.
Main Methods:
- GPR84 expression analysis in human and murine macrophages.
- Assessment of cytokine production, reactive oxygen species (ROS) generation, and phagocytosis upon agonist treatment.
- In vivo efficacy testing in a subcutaneous MC38 colorectal cancer model.
Main Results:
- GPR84 agonists increased pro-inflammatory cytokines and ROS in human THP-1 macrophages.
- No pro-inflammatory responses, ROS production, or phagocytosis were observed in murine macrophages.
- Both agonists failed to inhibit tumor growth in the MC38 model despite systemic exposure.
Conclusions:
- Current GPR84 agonists do not effectively promote anti-cancer macrophage activity.
- These findings limit the potential of GPR84 agonists as colorectal cancer therapies.
