2025-04-11 京都大学
<関連情報>
- https://www.kyoto-u.ac.jp/ja/research-news/2025-04-11-1
- https://www.kyoto-u.ac.jp/sites/default/files/2025-04/web_2504_Tsukamoto-fc4a148a5d3eb8613fb120ee2debe6ad.pdf
- https://insight.jci.org/articles/view/186483
ICOS+CD4 T細胞が抗PD-1療法による肺病変の高い感受性を規定する ICOS+CD4 T cells define a high susceptibility to anti-PD-1 therapy-induced lung pathogenesis
Mari Yokoi, Kosaku Murakami, Tomonori Yaguchi, Kenji Chamoto, Hiroaki Ozasa, Hironori Yoshida, Mirei Shirakashi, Katsuhiro Ito, Yoshihiro Komohara, Yukio Fujiwara, Hiromu Yano, Tatsuya Ogimoto, Daiki Hira, Tomohiro Terada, Toyohiro Hirai, and Hirotake Tsukamoto
Journal of Clinical Investigation Insight: JCI Published: April 8, 2025
DOI:https://doi.org/10.1172/jci.insight.186483
Graphical Abstract
Abstract
Managing immune-related adverse events (irAEs) caused by cancer immunotherapy is essential for developing effective and safer therapies. However, cellular mechanism(s) underlying organ toxicity during anti-PD-(L)1 therapy remain unclear. Here, we investigated the effect of chronological aging on anti-PD-(L)1 therapy-induced irAE-like lung toxicity, utilizing tumor-bearing aged mice. Anti-PD-(L)1 therapy facilitated ectopic infiltration of T and B cells, and antibody deposition in lung of aged but not young mice. Adoptive transfer of aged lung-derived CD4 T cells into TCR-deficient mice revealed that both pathogenic CD4 T cells and aged host environment were necessary for the irAE-inducible responses. Single-cell transcriptomics of lung-infiltrating cells in aged mice demonstrated that anti-PD-(L)1 therapy elicited ICOS+CD4 T-cell activation. Disruption of ICOS-ICOSL interaction attenuated germinal center B-cell differentiation and subsequent lung damage, which were overcome by local administration of IL-21 in the lung of anti-PD-1 therapy-treated aged mice. Therefore, ICOS+CD4 T cells elicited under aged environment exacerbated aberrant immune responses and the subsequent lung dysfunction. Consistent with the findings from mouse model, ICOS up-regulation in CD4 T cells was associated with later irAE incidence in patients with cancer. These finding will help development of useful strategies for irAE management in cancer patients, many of whom are elderly.
