Exploring the therapeutic potential of immune checkpoint modulation in preclinical models of inflammatory diseases

Atherosclerosis, a lipid-driven inflammatory disease of large arteries, is a leading cause of cardiovascular disease. While lipid-lowering therapies are effective, some patients retain a residual inflammatory risk, highlighting the need for alternative anti-inflammatory treatments. This thesis investigates the therapeutic potential of immune checkpoint modulation in preclinical models of inflammatory diseases.
The first part examines the role of immune checkpoints in T cell-mediated inflammation. It begins by exploring E3 ubiquitin ligases as intracellular immune checkpoints, focusing on the E3 ubiquitin ligase CBL-B. We demonstrate that CBL-B deletion reduces atherosclerosis in mice while promoting T cell activation and T cell plaque infiltration. Next, we identify a novel binding partner for the immune checkpoint CD40L, RACK1, and reveal its role in Th1 cell stabilization. A systematic review and meta-analysis follow, showing that cancer-targeted immune checkpoint inhibitors can accelerate atherosclerosis. Finally, we explore the hypothesis that statins may enhance the efficacy of these immune checkpoint inhibitors.
The second part evaluates CD40-TRAF6-targeted therapy, which has shown promise in atherosclerotic mice. Extending this research, we investigate its effects in atherosclerotic pigs, providing an initial analysis, and in secondary haemophagocytic lymphohistiocytosis (sHLH), an acute hyperinflammatory condition. A literature review highlights the roke of immune checkpoints in sHLH, and a pilot study implicates CD40 in the inflammatory response.
Overall, this thesis advances understanding of immune checkpoints and highlights their potential as therapeutic targets in inflammatory diseases.