Tu176 - Impact of Incretin Mimetics on Circulating Immune Cells in Humans

Abstract Text: In 2024, the weight loss drug class, GLP-1 receptor agonists (AKA: incretin mimetics or IM), accounted for up to 5% of all prescriptions written in the US. With indications for type 2 diabetes mellitus, obesity, obesity-related cardiovascular disease, sleep apnea, and other conditions, the application of these drugs alone or in combination is rapidly expanding. Obesity is an established risk factor for multiple cancers and induces immunosuppression by directly compromising the function of adaptive immune cells. However, it is currently unknown if the short- or long-term usage of IM impacts the function of immune cells in non-malignant settings or alters anti-tumor immunity.
To determine any direct effects of IM on circulating immunity, we mined data from the Human Protein Atlas, which revealed that naïve T-cells and NK cells express genes coding for GLP-1 or GIP receptors. We performed flow cytometry on healthy human peripheral blood mononuclear cells, which demonstrated that a subset of circulating T-cells expressed low levels of GLP-1R on their surface while monocytes expressed high levels of GCGR, both of which increased in samples from obese donors. Functionally, we also found that stimulating human T-cells with the IMs semaglutide and tirzepatide significantly reduced the surface expression of the immunoinhibitory proteins TIM3 and LAG3.
Based on these observations, and mounting evidence that IM may lower cancer risk, we will use mouse models of obesity and human samples to test our central hypothesis that IM will augment T-cell function and enhance T-cell-mediated elimination of cancer cells in settings of obesity.