Progenitor exhausted PD-1+ T cells are cellular targets of immune checkpoint inhibition in atherosclerosis.
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Mulholland M, Chalou A, Andersson SHA, Depuydt MAC, Yu Y, Lin S, Tallbäck K, Ericsson A, Jakobsson G, de Mol J, Kryvokhyzha D, Lichtman AH, Foks AC, Schiopu A, Björkbacka H, Slütter B, Gisterå A, Engelbertsen D
Nat Cardiovasc Res 4 (10) 1311-1328 [2025-10-00; online 2025-10-07]
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-1intSlamf6+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-1high T cell accumulation, IFNγ production, formation of lymphocyte foci and neutrophil recruitment. Depletion of PD-1high T cells prior to PD-1 blockade did not impede T cell recruitment, suggesting a role for progenitor exhausted PD-1int 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.
Clinical Genomics Lund [Service]
PubMed 41057609
DOI 10.1038/s44161-025-00713-2
Crossref 10.1038/s44161-025-00713-2
pmc: PMC12520982
pii: 10.1038/s44161-025-00713-2