Chimeric Antigen Receptor Regulatory T Cells Targeted Against Oxidized Low-Density Lipoprotein Reduce Atherosclerotic Plaque Development
Robert D. Schwab, David Degaramo, Seok Jae Hong, Xin Bi, Aisha Faruqi, William Aguilar, Shawna K. Brookens, John T. Keane, Fang Liu, Kiran Musunuru, Daniel J. Rader, Avery D. Posey
Abstract
BACKGROUND: Cardiovascular disease caused by atherosclerosis is responsible for 18 million deaths annually, highlighting a need for new medical therapies, especially for patients who are not eligible for percutaneous intervention. Atherosclerosis is driven by the accumulation of low-density lipoprotein and the formation of foam cells, accompanied by oxidative stress and the accumulation of oxidized low-density lipoprotein (OxLDL), a proinflammatory molecule. Lowering low-density lipoprotein levels is the mainstay of current treatment, along with blood pressure control and lifestyle changes, but to date, it has not been feasible to specifically target inflammatory pathways contributing to plaque development without considerable systemic side effects. Over the past decade, chimeric antigen receptor T cells have been used to treat cancer, resolve cardiac fibrosis, and restore immune balance in autoimmune diseases. In some instances, regulatory T cells endowed with chimeric antigen receptor (CAR Tregs) have been developed to treat autoimmunity through antigen-specific immunosuppression. METHODS: Using an inducible regulatory T cell platform, we created an anti-OxLDL-specific CAR Treg therapy and evaluated cell- and cytokine-mediated immunosuppression to reduce macrophage foam cell formation in vitro. We then tested murine anti-OxLDL CAR Tregs in immunocompetent mouse models of hyperlipidemia and atherosclerosis. RESULTS: Anti-OxLDL CAR Tregs reduced macrophage foam cell formation in vitro and significantly inhibited atherosclerotic plaque formation in vivo in immunocompetent mouse models. CONCLUSIONS: Anti-OxLDL CAR Tregs mitigate inflammation and plaque deposition associated with OxLDL and may offer a new therapeutic option for atherosclerosis.