Megan Mulholland, Anthi Chalou, Sandra Andersson, Marie A.C. Depuydt, Yinda Yu, Shiying Lin, Klara Tallbäck, Astrid Ericsson, Gabriel Jakobsson, Jill de Mol, Dmytro Kryvokhyzha, Andrew Lichtman, Amanda C. Foks, Alexandru Șchiopu, Harry Björkbacka, Bram Slütter, Anton Gisterå, Daniel Engelbertsen
Abstract Immune checkpoint inhibitors (ICIs), targeting checkpoint receptors such as programmed cell death protein 1 (PD-1), are associated with increased risk of cardiovascular events, but the underlying mechanisms remain poorly understood. Here we show that PD-1 + T cells from murine atherosclerotic aortas mainly display a progenitor exhausted phenotype (PD-1 int Slamf6 + Tim3 − ), produce IFNγ in vivo, exhibit signs of recent proliferation and maintain polyfunctionality. PD-1 blockade induced marked changes in plaque immune phenotype, with increased PD-1 high T cell accumulation, IFNγ production, formation of lymphocyte foci and neutrophil recruitment. Depletion of PD-1 high T cells prior to PD-1 blockade did not impede T cell recruitment, suggesting a role for progenitor exhausted PD-1 int T cells in ICI-driven T cell plaque accumulation. Human circulating PD-1 + T cells produced IFNγ and were associated with subclinical coronary atherosclerosis. Our studies highlight IFNγ-producing PD-1 + T cells as a potential key immune cell population mediating increased cardiovascular risk in patients with cancer receiving ICI.