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

Mulholland, Megan LU ; Chalou, Anthi LU ; Andersson, Samuel H A LU orcid ; Depuydt, Marie A C LU ; Yu, Yinda ; Lin, Shiying LU ; Tallbäck, Klara ; Ericsson, Astrid LU ; Jakobsson, Gabriel LU and de Mol, Jill , et al. (2025) In Nature Cardiovascular Research 4(10). p.1311-1328
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 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,... (More)

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 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Cardiovascular Research
volume
4
issue
10
pages
1311 - 1328
publisher
Nature Publishing Group
external identifiers
  • scopus:105018846142
  • pmid:41057609
ISSN
2731-0590
DOI
10.1038/s44161-025-00713-2
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
02df2a4d-7b28-4209-80f4-9c184546a922
date added to LUP
2025-10-13 09:08:58
date last changed
2025-12-19 16:20:06
@article{02df2a4d-7b28-4209-80f4-9c184546a922,
  abstract     = {{<p>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 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. </p>}},
  author       = {{Mulholland, Megan and Chalou, Anthi and Andersson, Samuel H A and Depuydt, Marie A C and Yu, Yinda and Lin, Shiying and Tallbäck, Klara and Ericsson, Astrid and Jakobsson, Gabriel and de Mol, Jill and Kryvokhyzha, Dmytro and Lichtman, Andrew H and Foks, Amanda C and Schiopu, Alexandru and Björkbacka, Harry and Slütter, Bram and Gisterå, Anton and Engelbertsen, Daniel}},
  issn         = {{2731-0590}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{10}},
  pages        = {{1311--1328}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cardiovascular Research}},
  title        = {{Progenitor exhausted PD-1<sup>+</sup> T cells are cellular targets of immune checkpoint inhibition in atherosclerosis}},
  url          = {{http://dx.doi.org/10.1038/s44161-025-00713-2}},
  doi          = {{10.1038/s44161-025-00713-2}},
  volume       = {{4}},
  year         = {{2025}},
}