Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China.
Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, China.
Front Immunol. 2023 Mar 7;14:1139517. doi: 10.3389/fimmu.2023.1139517. eCollection 2023.
Despite accumulated evidence in T-cell exhaustion in acute myeloid leukemia (AML), the immunotherapeutic targeting exhausted T cells such as programmed cell death protein 1 (PD-1) blockade in AML failed to achieve satisfying efficacy. Characteristics of exhausted T cells in AML remained to be explored.
Phenotypic analysis of T cells in bone marrow (BM) using flow cytometry combining senescent and exhausted markers was performed in de novo AML patients and healthy donors as well as AML patients with complete remission (CR). Functional analysis of T-cell subsets was also performed in de novo AML patients using flow cytometry.
T cells experienced a phenotypic shift to terminal differentiation characterized by increased loss of CD28 expression and decrease of naïve T cells. Additionally, lack of CD28 expression could help define a severely exhausted subset from generally exhausted T cells (PD-1TIGIT). Moreover, CD28- subsets rather than CD28+ subsets predominantly contributed to the significant accumulation of PD-1TIGIT T cells in AML patients. Further comparison of de novo and CR AML patients showed that T-cell exhaustion status was improved after disease remission, especially in CD28+ subsets. Notably, higher frequency of CD28-TIGIT-CD4 T cells correlated with the presence of minimal residual disease in AML-CR group. However, the correlation between CD28- exhausted T cells and cytogenetic risk or white blood cell count was not observed, except for that CD28- exhausted CD4 T cells correlated with lymphocyte counts. Intriguingly, larger amount of CD28-TGITICD8 T cells at diagnosis was associated with poor treatment response and shorter leukemia free survival.
In summary, lack of CD28 expression defined a severely exhausted status from exhausted T cells. Accumulation of CD28- exhausted T cells was linked to occurrence of AML, and correlated to poor clinical outcome. Our data might facilitate the development of combinatory strategies to improve the efficacy of PD-1 blockade in AML.
尽管在急性髓系白血病（AML）中已经积累了 T 细胞耗竭的证据，但针对耗竭 T 细胞的免疫治疗，如程序性细胞死亡蛋白 1（PD-1）阻断，在 AML 中的疗效仍不尽人意。AML 中耗竭 T 细胞的特征仍有待探索。
使用流式细胞术结合衰老和耗竭标志物对初诊 AML 患者、健康供者和完全缓解（CR）的 AML 患者的骨髓（BM）T 细胞进行表型分析。还使用流式细胞术对初诊 AML 患者的 T 细胞亚群进行功能分析。
T 细胞经历了表型转变，表现为 CD28 表达缺失增加和幼稚 T 细胞减少的终末分化特征。此外，缺乏 CD28 表达有助于从一般耗竭的 T 细胞（PD-1TIGIT）中定义一个严重耗竭的亚群。此外，在 AML 患者中，CD28-亚群而非 CD28+亚群主要导致 PD-1TIGIT T 细胞的显著累积。进一步比较初诊和 CR AML 患者发现，疾病缓解后 T 细胞耗竭状态得到改善，特别是在 CD28+亚群中。值得注意的是，AML-CR 组中 CD28-TIGIT-CD4 T 细胞的频率较高与微小残留病的存在相关。然而，除了 CD28-耗尽的 CD4 T 细胞与淋巴细胞计数相关外，CD28-耗尽的 T 细胞与细胞遗传学风险或白细胞计数之间没有观察到相关性。有趣的是，初诊时更多的 CD28-TGITICD8 T 细胞与治疗反应差和无白血病生存时间短相关。
总之，缺乏 CD28 表达从耗竭的 T 细胞中定义了一个严重的耗竭状态。CD28-耗尽 T 细胞的积累与 AML 的发生有关，并与不良的临床结局相关。我们的数据可能有助于制定联合策略，以提高 AML 中 PD-1 阻断的疗效。
