Communications Biology (Sep 2023)

ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis

  • Haruki Horiguchi,
  • Tsuyoshi Kadomatsu,
  • Tomoya Yamashita,
  • Shinsei Yumoto,
  • Kazutoyo Terada,
  • Michio Sato,
  • Jun Morinaga,
  • Keishi Miyata,
  • Yuichi Oike

DOI
https://doi.org/10.1038/s42003-023-05338-4
Journal volume & issue
Vol. 6, no. 1
pp. 1 – 12

Abstract

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Abstract Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy advances rapidly in the clinic. Despite their therapeutic benefits, ICIs can cause clinically significant immune-related adverse events (irAEs), including myocarditis. However, the cellular and molecular mechanisms regulating irAE remain unclear. Here, we investigate the function of Angiopoietin-like protein 2 (ANGPTL2), a potential inflammatory mediator, in a mouse model of ICI-related autoimmune myocarditis. ANGPTL2 deficiency attenuates autoimmune inflammation in these mice, an outcome associated with decreased numbers of T cells and macrophages. We also show that cardiac fibroblasts express abundant ANGPTL2. Importantly, cardiac myofibroblast-derived ANGPTL2 enhances expression of chemoattractants via the NF-κB pathway, accelerating T cell recruitment into heart tissues. Our findings suggest an immunostimulatory function for ANGPTL2 in the context of ICI-related autoimmune inflammation and highlight the pathophysiological significance of ANGPTL2-mediated cardiac myofibroblast/immune cell crosstalk in enhancing autoimmune responses. These findings overall provide insight into mechanisms regulating irAEs.