Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham.
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Centre for Computational Biology, University of Birmingham, Birmingham.
Haematologica. 2023 Feb 1;108(2):433-443. doi: 10.3324/haematol.2021.280497.
Allogeneic stem cell transplantation is used widely in the treatment of hematopoietic malignancy. However, relapse of malignant disease is the primary cause of treatment failure and reflects loss of immunological graft-versus-leukemia effect. We studied the transcriptional and phenotypic profile of CD8+ T cells in the first month following transplantation and related this to risk of subsequent relapse. Single cell transcriptional profiling identified five discrete CD8+ T-cell clusters. High levels of T-cell activation and acquisition of a regulatory transcriptome were apparent in patients who went on to suffer disease relapse. A relapse-associated gene signature of 47 genes was then assessed in a confirmation cohort of 34 patients. High expression of the inhibitory receptor CD94/NKG2A on CD8+ T cells within the first month was associated with 4.8 fold increased risk of relapse and 2.7 fold reduction in survival. Furthermore, reduced expression of the activatory molecule CD96 was associated with 2.2 fold increased risk of relapse and 1.9 fold reduction in survival. This work identifies CD94 and CD96 as potential targets for CD8-directed immunotherapy in the very early phase following allogeneic transplantation with the potential to reduce long term relapse rates and improve patient survival.
异基因造血干细胞移植广泛用于治疗血液系统恶性肿瘤。然而，恶性疾病的复发是治疗失败的主要原因，反映了免疫移植物抗白血病效应的丧失。我们研究了移植后第一个月 CD8+T 细胞的转录和表型特征，并将其与随后复发的风险相关联。单细胞转录谱分析确定了五个离散的 CD8+T 细胞簇。在随后发生疾病复发的患者中，T 细胞激活水平高，并获得调节性转录组。然后在 34 名患者的确认队列中评估了 47 个基因的复发相关基因特征。在第一个月内 CD8+T 细胞上抑制性受体 CD94/NKG2A 的高表达与复发风险增加 4.8 倍和生存率降低 2.7 倍相关。此外，活化分子 CD96 的表达降低与复发风险增加 2.2 倍和生存率降低 1.9 倍相关。这项工作确定了 CD94 和 CD96 作为异基因移植后早期 CD8 定向免疫治疗的潜在靶点，有可能降低长期复发率并提高患者生存率。
