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

## TL;DR

This study identifies PD-1+ T cells as a key immune cell population linked to increased cardiovascular risk from immune checkpoint inhibitors.

## Contribution

The study identifies progenitor exhausted PD-1+ T cells as a novel cellular target of immune checkpoint inhibition in atherosclerosis.

## Key findings

- PD-1+ T cells in atherosclerotic aortas produce IFNγ and maintain polyfunctionality.
- PD-1 blockade increases T cell accumulation and IFNγ production in atherosclerotic plaques.
- Human PD-1+ T cells are associated with subclinical coronary atherosclerosis.

## 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-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.

Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.