背景:先前的研究表明,巨噬细胞介导的红细胞增多与急性髓性白血病(AML)的免疫抑制有关。然而,在AML中,有效细胞增多的调节作用尚不清楚,需要进一步阐明.
方法:我们首先根据表达矩阵确定了关键的有效细胞相关基因(ERGs)。通过共识聚类算法获得与细胞增殖相关的分子亚型。进一步评估了分子亚型之间的免疫景观和生物学过程的差异。构建Efferocytosis评分模型,对AML患者的分子亚型进行量化,评价其在预后预测和治疗决策中的价值。
结果:鉴定出三种不同的与细胞增殖相关的分子亚型,免疫沙漠,和基于免疫景观特征的免疫抑制亚型。我们评估了不同分子亚型之间临床和生物学特征的差异,而构建的Efferocytosis评分模型可以有效地量化亚型。低红细胞增多症评分与免疫激活和降低突变频率相关,患者预后较好。高的红细胞增多评分反映了免疫衰竭,肿瘤标志物途径的活性增加,预后不良。在六个AML队列中证实了Efferocytosis评分模型的预后预测价值。表现出高红细胞增多症评分的患者可能从抗PD-1免疫疗法获得治疗益处,而那些具有低红细胞增多症评分的患者倾向于对化疗表现出更高的敏感性。对离体AML细胞中的治疗数据的分析揭示了一组药物在不同的有效细胞增殖评分组间的敏感性存在显著差异。最后,我们在一个临床队列中验证了模型基因表达.
结论:这项研究表明,在形成AML免疫微环境的多样性和复杂性方面,细胞凋亡起着不可忽视的作用。评估个体中与红细胞增多相关的分子亚型将有助于增强我们对AML免疫景观表征的理解,并指导建立更有效的临床治疗策略。
BACKGROUND: Previous studies have shown that macrophage-mediated
efferocytosis is involved in immunosuppression in acute myeloid leukemia (AML). However, the regulatory role of
efferocytosis in AML remains unclear and needs further elucidation.
METHODS: We first identified the key efferocytosis-related genes (ERGs) based on the expression matrix.
Efferocytosis-related molecular subtypes were obtained by consensus clustering algorithm. Differences in immune landscape and biological processes among molecular subtypes were further evaluated. The
efferocytosis score model was constructed to quantify molecular subtypes and evaluate its value in prognosis prediction and treatment decision-making in AML.
RESULTS: Three distinct efferocytosis-related molecular subtypes were identified and divided into immune activation, immune desert, and immunosuppression subtypes based on the characteristics of the immune landscape. We evaluated the differences in clinical and biological features among different molecular subtypes, and the construction of an efferocytosis score model can effectively quantify the subtypes. A low efferocytosis score is associated with immune activation and reduced mutation frequency, and patients have a better prognosis. A high efferocytosis score reflects immune exhaustion, increased activity of tumor marker pathways, and poor prognosis. The prognostic predictive value of the
efferocytosis score model was confirmed in six AML cohorts. Patients exhibiting high efferocytosis scores may derive therapeutic benefits from anti-PD-1 immunotherapy, whereas those with low efferocytosis scores tend to exhibit greater sensitivity towards chemotherapy. Analysis of treatment data in ex vivo AML cells revealed a group of drugs with significant differences in sensitivity between different efferocytosis score groups. Finally, we validated model gene expression in a clinical cohort.
CONCLUSIONS: This study reveals that efferocytosis plays a non-negligible role in shaping the diversity and complexity of the AML immune microenvironment. Assessing the individual efferocytosis-related molecular subtype in individuals will help to enhance our understanding of the characterization of the AML immune landscape and guide the establishment of more effective clinical treatment strategies.