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

Summary

In aged tumor-bearing mice, anti–PD-(L)1 therapy induces ICOS+ CD4+ T cell activation that drives germinal center B cell responses and lung injury mimicking irAEs; blocking ICOS–ICOSL attenuates damage, while local IL-21 restores it. Adoptive transfer and single-cell data show both aged host milieu and pathogenic CD4+ T cells are required. In patients, CD4+ T-cell ICOS upregulation correlates with later irAE incidence.

Key Findings

• Anti–PD-(L)1 therapy induced ICOS+ CD4+ T cell activation and ectopic T/B cell infiltration with antibody deposition in aged, not young, mouse lungs.
• Blocking ICOS–ICOSL reduced germinal center B cell differentiation and lung injury; local IL-21 administration reversed protection.
• Adoptive transfer showed both pathogenic aged lung CD4+ T cells and an aged host environment were required for irAE-like responses.
• In cancer patients, increased ICOS expression on CD4+ T cells associated with later irAE incidence.

Clinical Implications

Monitoring ICOS expression on CD4+ T cells could anticipate lung irAEs in patients on anti–PD-1 therapy, especially the elderly. Therapeutically, modulating the ICOS–ICOSL axis or downstream IL-21 signaling may mitigate lung toxicity without broadly suppressing antitumor immunity.

Limitations

• Predominantly preclinical murine data; generalizability across tumor types and human heterogeneity remains to be established.
• Clinical cohort details (sample size, timing, confounders) for ICOS association were limited in the abstract.

Future Directions

Prospective studies to validate ICOS+ CD4+ T cells as predictive biomarkers and trials testing ICOS–ICOSL modulation or IL-21 pathway interventions to prevent/manage lung irAEs, with stratification by age.