The impact of incretin mimetics on systemic immunity and T-cell activation 3994

Abstract Description Incretin mimetics (IMs), including GLP-1 and GIP receptor agonists, have recently emerged as groundbreaking therapies for obesity and type 2 diabetes (T2D). Despite their success, little is known about how these drugs impact cancer progression and the immunosurveillance of malignant cells. Data mined from the Human Protein Atlas demonstrated expression of receptors for GLP-1 (GLP-1R) and GIP (GIPR) on normal T-cells and NK cells. Further querying showed widespread expression of these receptors across B-cell acute lymphoblastic leukemia (B-ALL) and pancreatic cancer (PANC) cell lines, and their expression in primary samples was associated with better patient prognoses. We performed flow cytometry on human PBMCs from donors across a spectrum of age, ethnicity, and BMI, demonstrating modest expression of GLP-1R on subsets of circulating T cells and striking expression of the glucagon receptor (GCGR) on classical monocytes. GCGR-expressing monocytes were enhanced in donors with obesity and had lower antigen presentation and adhesion marker expression. We then isolated and stimulated T-cells from PBMCs for 72 hours in combination with the IMs semaglutide and tirzepatide, showing IMs lower the expression of immunosuppressive proteins on CD8 T-cells in a BMI dependent fashion. Taken together, we demonstrate a capacity for IMs to directly impact circulating immune cells, which may augment T-cell function and enhance T-cell-mediated elimination of cancer cells in settings of obesity. Funding Sources Supported by awards from The Gates Foundation, The Patten Davis Foundation, The University of Colorado Cancer Center THI Program Pilot Funding, and the Aflac Cancer and Blood Disorders Center. Topic Categories Immune Mechanisms of Human Disease (HUM)