Distinct Inflammatory Cytotoxic T Lymphocyte Populations Mediate PD-1 Blockade–Induced Immune-Related Adverse Events in Multiple Organs

Abstract Immune checkpoint blockade–induced immune-related adverse events (irAE) hamper the application of this revolutionary antitumor therapeutic strategy. In this study, we explored the mechanisms driving irAEs by profiling the immune ecosystem of major irAE-affected organs at the single-cell scale. The analysis identified 3 populations of cytotoxic T lymphocytes that mediate antitumor immunity (CTL1) or that induce irAE in the gut (CTLirAE-I) or in multiple other organs (CTLirAE-II). Interleukin–JAK1 signaling was specifically activated in the CTLirAE-II population upon PD-1 blockade. Targeting JAK1 remarkably relieved the irAEs in the heart and lung without compromising antitumor efficacy. Tracking T-cell receptor sequence and transcriptome showed that CTLirAE-II and CTL1 populations originated from lymph node progenitor cells, whereas the CTLirAE-I population was derived from tissue-resident memory T cells. Moreover, irAEs could be monitored by assessing the CTLirAE-II population in circulation. In conclusion, this study elucidates the landscape of cellular changes in irAEs across multiple organs after immunotherapy and proposes strategies for relieving irAE symptoms and facilitating diagnosis. Significance: Dissecting PD-1 blockade-induced immune-related adverse events across multiple organs at a single-cell scale elucidates regulators of pathogenic progression and clonal evolution, providing strategies for diagnosis and treatment without impairing antitumor efficacy.