The cellular atlas of senescent lineages in radiation- or immunotherapy-induced lung injury by single-cell RNA-sequencing analysis

Immune therapy and radiotherapy have a central role in treating various malignant tumors. However, immune checkpoint inhibitors have been reported to increase pulmonary toxicity and cause a higher incidence of severe pneumonitis in the irradiated lungs in patients with lung cancer. Moreover, the mechanism of the lung injury induced by immunotherapy and irradiation involves a complex interplay of cell types and signaling pathways, which remains unclear. With the unbiased nature of single-cell RNA sequencing technology, we comprehensively define cell types, mechanisms, and mediators driving the pathological remodeling in response to lung injury caused by IR or ICI at different time points. Thirty distinct cell subsets were identified in this study, encompassing 75,396 cells. The comprehensive investigation of cell-cell cross talk indicated that the monokine signals derived from a senescent subpopulation of fibroblasts were dominantly increased after injury. With independent analysis strategies, subtypes of fibroblasts, alveolar epithelial cells, B cells, and myeloid immune cells were found to be functionally pathological and highly expressing senescent signatures, especially Apoe, during injury response. Together, these high-resolution transcriptomic data provide novel insights into cellular processes involved in the immunotherapy- or irradiation-induced lung injury, which might offer therapeutic opportunities to prevent lung injury.