PO.BCS01.16 · 生物信息与计算
基因组驱动因素和免疫冷微环境与中国儿童B-ALL复发相关
Genomic drivers and an immune-cold microenvironment are associated with relapse in Chinese pediatric B-ALL
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：复发仍然是儿童B细胞急性淋巴细胞白血病（B-ALL）的一大挑战。本研究旨在识别驱动治疗失败并与中国儿童B-ALL患者复发和不良无事件生存期（EFS）相关的特定基因组和细胞标志物。
方法：我们对105例中国儿童B-ALL患者（包括13例EFS事件[复发加死亡]病例）的队列进行了整合的多组学分析。该队列采用超深度基因panel测序（N=87）、单细胞RNA测序（scRNA-seq，N=52）和VDJ测序（N=40）进行分析。我们整合了基因组、转录组和免疫组库数据，以识别与复发和EFS相关的生物标志物。关联性采用Fisher精确检验、Wilcoxon秩和检验和Cox回归进行检验。
结果：我们的scRNA-seq和VDJ-seq分析揭示了复发的细胞图景。我们发现B-ALL原始细胞比例与BCR克隆性之间呈正相关，T细胞比例与TCR克隆性之间呈负相关（p=0.041）。值得注意的是，复发患者表现出更高的BCR克隆性，但TCR组库高度多克隆，提示免疫失效。
我们发现，经整理的ALL驱动基因panel中的突变与复发状态（p=0.033）和更高的B-ALL原始细胞百分比（p=0.013）显著相关。而更高的ALL驱动基因VAF负荷表型与复发状态相关（p=0.006）。
研究发现，非复发患者表现出"免疫热"表型，其特征是显著更高的T细胞耗竭和细胞毒性评分（p<0.001）。这种活跃免疫参与状态与PD-1/PD-L1通路相关。复发则与"免疫冷"状态相关，缺乏这种活跃的T细胞参与。
最后，生存分析和KM图证实了这些发现的预后意义。ALL驱动基因的存在与不良无事件生存期显著相关（p=0.021）。
结论：我们的发现揭示了通往不良预后的生物学通路。ALL驱动基因与高B-ALL原始细胞负荷相关。这种高危状态与患者复发密切相关，其特征是"免疫冷"微环境，即缺乏在非复发患者中所见的PD-L1介导的T细胞耗竭和细胞毒性特征。
查看英文原文 English abstract
Background: Relapse remains a major challenge in pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL). This study aims to identify the specific genomic and cellular markers that drive treatment failure and are associated with relapse and poor Event-Free Survival (EFS) in Chinese pediatric B-ALL patients.
Methods: We performed an integrated multi-omic analysis on a cohort of 105 Chinese pediatric B-ALL patients, including 13 EFS Event (relapse plus died) cases. The cohort was profiled using ultra-deep gene panel sequencing (N=87), single-cell RNA-sequencing (scRNA-seq, N=52), and VDJ-sequencing (N=40). We integrated genomic, transcriptomic, and immune repertoire data to identify biomarkers associated with relapse and EFS. Associations were tested using Fisher's Exact Test, the Wilcoxon rank-sum test, and Cox regression.
Results: Our scRNA-seq and VDJ-seq analyses revealed the cellular landscape of relapse. We found a positive correlation between B-ALL blast proportion and BCR clonality and a negative correlation between T-cell proportion and TCR clonality (p=0.041). Notably, relapsed patients showed a higher BCR clonality but a highly polyclonal TCR repertoire, suggesting immune failure.
We identified that mutations in a curated panel of ALL-Drivers was significantly associated with relapse status (p=0.033) and a higher B-ALL blast percentage (p=0.013). And the higher ALL-Drivers VAF burden phenotype correlates with relapse status (p=0.006).
The non-relapse patients were found exhibited an “immune-hot" phenotype, characterized by significantly higher T-cell exhaustion and cytotoxicity scores (p<0.001). This state of active immune engagement is associated with PD-1/PD-L1 pathway. Relapse was associated with an "immune-cold" state, lacking this active T-cell engagement.
Finally, survival analysis and KM plot confirmed the prognostic significance of these findings. The presence of an ALL-Driver is significantly associated with poor Event-Free Survival (p=0.021).
Conclusion: Our findings reveal a biological pathway to poor prognosis. ALL-Drivers are linked to a high B-ALL blasts burden. This high-risk state is strongly correlated with patient relapse and is characterized by an "immune-cold" microenvironment, defined by the absence of the PD-L1 mediated T-cell exhaustion and cytotoxicity signature seen in non-relapsed patients.
利益披露 Disclosure
D. Yu, None..
Y. Hu, None..
X. Tang, None..
J. Wang, None..
J. Wang, None..
J. Xiao, None.