Immune checkpoint landscape of human atherosclerosis and influence of cardiometabolic factors
José Gabriel Barcia Durán, Dayasagar Das, Michael Gildea, Letizia Amadori, Morgane Gourvest, Ravneet Kaur, Natalia Eberhardt, Panagiotis Smyrnis, Burak Cılhoroz, Swathy Sajja, Karishma Rahman, Dawn Fernandez, Peter L. Faries, Navneet Narula, R. Vanguri, Ira J. Goldberg, Edward A. Fisher, Jeffrey S. Berger, Kathryn J. Moore, Chiara Giannarelli
Abstract
Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7+FSCN1+ dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors. Barcia Durán, Dayasagar, et al. map the expression of immune checkpoints in human atherosclerosis and examine the influence of lipid-lowering treatments and type 2 diabetes to understand how immune checkpoint inhibitors worsen cardiovascular risk in survivors of cancer.