Clonal GZMK+CD8+ T cells are identified as a hallmark of the pathogenesis of cGVHD-induced bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation

作者：Yang Gao, Ruixiang Liu, Jiawei Shi, Wei Shan, Hongyu Zhou, Zhi Chen, Xiaoyan Yue, Jie Zhang, Yi Luo, Wenjue Pan, Xiujie Zhao, Xun Zeng, Weiwei Yin, Haowen Xiao · 发表于：EBioMedicine · 年份：2024 · DOI：10.1016/j.ebiom.2024.105535 · 被引用次数：19 · 研究领域：Hematopoietic Stem Cell Transplantation、Transplantation: Methods and Outcomes、Renal Transplantation Outcomes and Treatments

Background Bronchiolitis obliterans syndrome (BOS) is one of the most devastating outcomes of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This remains an area of unmet clinical need for optimal therapy for BOS patients partly due to the limited understanding of pathogenic mechanisms. Methods We collected blood samples from 22 patients with cGVHD and 11 patients without cGVHD following allo-HSCT. By applying a combination of mass cytometry (CyTOF), RNA-sequencing and the quantitative cytokine array, we discovered a new cellular hallmarker of patients with cGVHD-BOS. This finding was further validated in cGVHD-BOS murine models by using single-cell RNA sequencing (scRNA-seq) and paired single-cell V(D)J sequencing analyses. Findings We revealed that circulating Granzyme K (GZMK)-expressing CD8 + T cells with increased expression of CCR5 were accumulated in cGVHD-BOS patients, and GZMK can induce the expression of fibrosis-essential proteins, collagen type I alpha 1 chain (COL1A1) and fibronectin (FN1), in human fibroblasts. As compared to those of control mice, GZMK + CD8 + T cells in the lungs of cGVHD-BOS mice were undergoing significant infiltration and clonal hyperexpansion, with more cytotoxic, pro-inflammatory, migratory and exhausted phenotypes. Moreover, we screened small-molecule drugs and revealed that Bosutinib, the second-generation BCR-ABL1-targeting tyrosine kinase inhibitor (TKI), could inhibit G...