ICOS+CD4+ T cells define a high susceptibility to anti–PD-1 therapy–induced lung pathogenesis

• DOI: 10.1172/jci.insight.186483
• Publication Date: 2025-04-08T16:01:24Z
• Authors: 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; Hirotake Tsukamoto
• Keywords: Pathogenesis

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 therapy-induced irAE-like lung toxicity, utilizing tumor-bearing aged mice. Anti-PD-(L)1 facilitated ectopic infiltration T B cells, antibody deposition in but not young Adoptive transfer lung-derived CD4 cells into TCR-deficient mice revealed that both pathogenic host environment were necessary irAE-inducible responses. Single-cell transcriptomics lung-infiltrating demonstrated elicited ICOS+CD4 T-cell activation. Disruption ICOS-ICOSL interaction attenuated germinal center B-cell differentiation subsequent damage, which overcome local administration IL-21 anti-PD-1 therapy-treated Therefore, under exacerbated aberrant immune responses dysfunction. Consistent with findings from mouse model, ICOS up-regulation was associated later irAE incidence patients cancer. These finding will help development useful strategies management patients, many whom are elderly.