Progenitor exhausted PD-1+ T cells are cellular targets of immune checkpoint inhibition in atherosclerosis

Mulholland, M.: Chalou, A.; Andersson, S.H.A.; Depuydt, M.A.C.; Yu, Y.; Lin, S.; Tallbäck, K.; Ericsson, A.; Jakobsson, G.; Mol, J. de; Kryvokhyzha, D.; Lichtman, A.H.; Foks, A.C.; Schiopu, A.; Björkbacka, H.; Slütter, B.A.; Gisterå, A.; Engelbertsen, D.

doi:doi:10.1038/s44161-025-00713-2

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^intSlamf6⁺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...Show moreImmune 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^intSlamf6⁺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.Show less

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Progenitor exhausted PD-1+ T cells are cellular targets of immune checkpoint inhibition in atherosclerosis