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

Immune checkpoint blockade-induced immune-related adverse events (irAEs) hamper the application of this revolutionary anti-tumor therapeutic strategy. Here, we explored the mechanisms driving irAEs by profiling the immune ecosystem of major irAE-affected organs at the single-cell scale. The analysis identified three populations of cytotoxic T lymphocytes that mediate anti-tumor 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 the anti-tumor efficacy. Tracking TCR sequence and transcriptome showed that CTLirAE-II and CTL1 populations originated from lymph node progenitor cells, while 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 following immunotherapy and proposes strategies for relieving irAE symptoms and facilitating diagnosis.