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

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.