MADCAM-1 and TNF-α Expression Reduced in GPR4 Knockout Mice Given Immune Checkpoint Inhibitor Immunotherapy

Abstract

Immunotherapy medications have become very common in the field of oncology as an effective treatment against many forms of cancer. Patients who begin immunotherapy sometimes develop immune adverse-related events (irAEs), such as colitis or inflammation of the colon, forcing them to pause treatment temporarily or indefinitely. The occurrence of inflammation has been linked to pH-sensing G-protein coupled receptors (GPCRs), specifically GPR4, which acts as a pro-inflammatory receptor expressed mainly in vascular endothelial cells and blood vessel-rich tissues. Inflammatory cytokine TNF- is commonly upregulated in inflamed tissues containing the GPR4 receptor. Mucosal adhesion cell adhesion molecule-1 (MAdCAM-1) is also upregulated during inflammatory responses and is only expressed in mucosal or sub-mucosal regions of the colon, making the molecule a desirable target for preventing colitis. MAdCAM-1 interacts with leukocyte integrins on the cell's surface to direct leukocyte infiltration, further exacerbating inflammation. It was hypothesized that the lack of GPR4 could downregulate inflammatory cytokine TNF- and endothelial cell adhesion molecule MAdCAM-1 expression in inflamed tissues, leading to a decrease in the severity of immunotherapy-mediated colitis. Our results show that mice who contain the GPR4 receptor and were given an immune-checkpoint immunotherapy medication had increased TNF- and MAdCAM-1 expression compared to GPR4 knock-out and immunotherapy control groups. In the absence of GPR4, the severity of colitis was significantly reduced, as well as the levels of TNF-- and MAdCAM-1 expression. Conclusions from this research could be used in developing antagonists specifically targeting the GPR4 receptor as a possible approach to lessen the severity of colitis.