Distinct immune cell dynamics associated with immune-related adverse events during combined chemoradiation and immune checkpoint inhibitor therapy.

Abstract

Combining chemoradiotherapy with immunotherapy increases the risk of immune-related adverse events (irAEs), but the underlying mechanisms remain poorly understood. To address this, we conducted a longitudinal single-cell multi-omics analysis of patients with locally advanced cervical cancer. Here we show that the proportions of CD4⁺ and CD8⁺ terminally differentiated effector memory or effector T cells are elevated in patients with irAEs. Chemoradiotherapy reduces B cell clonality while increasing the abundance and somatic hypermutation frequencies of IgA⁺ and IgG⁺ B cells in irAE patients. In the myeloid compartment, combined treatment expands specific monocyte subclusters associated with irAEs. Spatial transcriptomics and immunofluorescence analyses further reveal that these irAE-associated immune cells aggregate within the tumor microenvironment. Finally, we develop the predictive models for irAEs and integrate them, along with all datasets, into a user-friendly data portal. Our findings suggest that chemoradiotherapy and immunotherapy exert distinct effects on different immune cells, contributing to irAE development.