ICOS+CD4+ T cells define a high susceptibility to anti–PD-1 therapy–induced lung 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 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 lungs 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 an 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 the ICOS-ICOSL interaction attenuated germinal center B cell differentiation and subsequent lung damage, which were overcome by local administration of IL-21 in the lungs of anti-PD-1 therapy-treated aged mice. Therefore, ICOS+CD4+ T cells elicited under an aged environment exacerbated aberrant immune responses and the subsequent lung dysfunction. Consistent with the findings from the mouse model, ICOS upregulation 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 patients with cancer, many of whom are elderly.