Cancer immunotherapy targeting the immune checkpoints, such as PD-1 (programmed cell death 1)/PD-L1
(programmed death-ligand 1) and CTLA-4 (cytotoxic T lymphocyte associated protein 4), has led to
significant anti-tumor effects and overall survival improvement in some cancer patients. Due to hyper-
activation of the immune system, however, cancer immunotherapy may also cause mild-to-severe and
sometimes life-threatening immune-related adverse events (irAEs). The commons types of inflammatory
and autoimmune irAEs include colitis/diarrhea, hepatitis, pneumonitis, thyroiditis, and other inflammatory
complications. These irAEs can result in significant morbidity and treatment discontinuation. Biological
factors that predispose patients to irAEs after cancer immunotherapy, however, are not well established.
Corticosteroids and other immunosuppressive drugs are typically used for the management of irAEs, but
some patients are refractory to these treatments. Moreover, systemic immunosuppression associated with
immunosuppressive drugs may interfere with the anti-cancer effects of immunotherapy and may also place
patients at risk for opportunistic infections such as pneumonia. It is, therefore, important to better
understand the mechanisms of irAEs and to develop novel approaches for the management of irAEs.
While most irAE research focuses on immune cells and inflammatory cytokines, this project is aimed to
interrogate the interface between blood vessels and leukocytes. The proton-sensing G-protein-coupled
receptor 4 (GPR4) is highly expressed in vascular endothelial cells and functions as a “gatekeeper” during
inflammatory responses via regulating the leukocyte-endothelium interaction. Our recent studies
demonstrate that activation of GPR4 stimulates the expression of numerous inflammatory genes in
endothelial cells (ECs) and increases leukocyte-EC adhesion. Interestingly, the gene expression of GPR4 is
increased by about 5-fold in the inflamed intestinal tissues of ulcerative colitis and Crohn's disease samples
when compared to the non-inflamed intestinal tissues. Inhibition of GPR4 has anti-inflammatory, anti-
nociceptive, and anti-angiogenic effects. However, the function and mechanism of GPR4 in irAEs and
cancer immunotherapy have not been studied.
In this project, we will investigate the role and mechanism of GPR4 in cancer immunotherapy and irAEs.
GPR4 knockout mice and GPR4 antagonist will be employed to unravel the function of GPR4 in vivo. Mice
with melanoma will be treated with anti-CTLA-4/anti-PD-1 immunotherapy in combination with GPR4
inhibition. Using the mouse model, we will (1) determine the role and mechanism of GPR4 in
immunotherapy-related colitis and other irAEs; (2) elucidate the effects of GPR4 blockade on anti-cancer