Poveda-Garavito Nathaly, Orozco Castaño Carlos A, Torres-Llanos Yulieth, Cruz-Rodriguez Nataly, Parra-Medina Rafael, Quijano Sandra, Zabaleta Jovanny, Combita Alba Lucia
Grupo de Investigación en Biología del Cáncer - Instituto Nacional de Cancerología, Bogotá, Colombia.
Grupo de Investigación Traslacional en Oncología - Instituto Nacional de Cancerología, Bogotá, Colombia.
Front Immunol. 2024 Nov 29;15:1473909. doi: 10.3389/fimmu.2024.1473909. eCollection 2024.
B-cell acute lymphoblastic leukemia (B-ALL) in adults often presents a poor prognosis. ID1 and ID3 genes have been identified as predictors of poor response in Colombian adult B-ALL patients, contributing to cancer development. In various cancer models, these genes have been associated with immune regulatory populations within the tumor immune microenvironment (TIME). B-ALL progression alters immune cell composition and the bone marrow (BM) microenvironment, impacting disease progression and therapy response. This study investigates the relationship between ID1 and ID3 expression, TIME dynamics, and immune evasion mechanisms in adult B-ALL patients.
This exploratory study analysed BM samples from 10 B-ALL adult patients diagnosed at the National Cancer Institute of Colombia. First, RT-qPCR was used to assess ID1 and ID3 expression in BM tumour cells. Flow cytometry characterised immune populations in the TIME. RNA-seq evaluated immune genes associatedwith B-ALL immune response, while xCell and CytoSig analysed TIME cell profiles and cytokines. Pathway analysis, gene ontology, and differential gene expression (DEGs) were examined, with functional enrichment analysis performed using KEGG ontology.
Patients were divided into two groups based on ID1 and ID3 expression, namely basal and overexpression. A total of 94 differentially expressed genes were identified between these groups, with top overexpressed genes associated with neutrophil pathways. Gene set enrichment analysis revealed increased expression of genes associated with neutrophil degranulation, immune response-related neutrophil activation, and neutrophil-mediated immunity. These findings correlated with xCell data. Overexpression group showed significant differences in neutrophils, monocytes and CD4+ naive T cells compared to basal group patients. Microenvironment and immune scores were also significantly different, consistent with the flow cytometry results. Elevated cytokine levels associated with neutrophil activation supported these findings. Validation was performed using the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) TCGA B-ALL cohorts.
These findings highlight significant differences in ID1 and ID3 expression levels and their impact on TIME populations, particularly neutrophil-related pathways. The results suggest a potential role for ID1 and ID3 in immune evasion in adult B-ALL, mediated through neutrophil activation and immune regulation.
成人B细胞急性淋巴细胞白血病（B-ALL）的预后通常较差。ID1和ID3基因已被确定为哥伦比亚成年B-ALL患者反应不佳的预测指标，对癌症发展有影响。在各种癌症模型中，这些基因与肿瘤免疫微环境（TIME）中的免疫调节群体有关。B-ALL的进展会改变免疫细胞组成和骨髓（BM）微环境，影响疾病进展和治疗反应。本研究调查了成年B-ALL患者中ID1和ID3表达、TIME动态与免疫逃逸机制之间的关系。
这项探索性研究分析了来自哥伦比亚国家癌症研究所诊断的10例成年B-ALL患者的骨髓样本。首先，使用逆转录定量聚合酶链反应（RT-qPCR）评估骨髓肿瘤细胞中ID1和ID3的表达。流式细胞术对TIME中的免疫群体进行了表征。RNA测序评估了与B-ALL免疫反应相关的免疫基因，而xCell和CytoSig分析了TIME细胞谱和细胞因子。进行了通路分析、基因本体论和差异基因表达（DEG）研究，并使用京都基因与基因组百科全书（KEGG）本体进行了功能富集分析。
根据ID1和ID3表达将患者分为两组，即基础表达组和过表达组。在这两组之间共鉴定出94个差异表达基因，过表达的前几位基因与中性粒细胞通路相关。基因集富集分析显示，与中性粒细胞脱颗粒、免疫反应相关的中性粒细胞激活和中性粒细胞介导的免疫相关的基因表达增加。这些发现与xCell数据相关。与基础表达组患者相比，过表达组在中性粒细胞、单核细胞和CD4+初始T细胞方面存在显著差异。微环境和免疫评分也有显著差异，与流式细胞术结果一致。与中性粒细胞激活相关的细胞因子水平升高支持了这些发现。使用治疗性适用研究生成有效治疗方法（TARGET）TCGA B-ALL队列进行了验证。
这些发现突出了ID1和ID3表达水平的显著差异及其对TIME群体的影响，特别是与中性粒细胞相关的通路。结果表明，ID1和ID3在成年B-ALL的免疫逃逸中可能发挥作用，通过中性粒细胞激活和免疫调节介导。
