PO.TB10.04 · 肿瘤生物学
多发性骨髓瘤自体干细胞移植大剂量美法仑预处理后可测量残留病灶的代谢相关因素
Metabolic correlates of measurable residual disease following high dose melphalan conditioning for autologous stem cell transplant in multiple myeloma
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摘要 Abstract
中文摘要
在多发性骨髓瘤（MM）中，大剂量美法仑（HDM）预处理后行自体干细胞移植（ASCT）可产生持久缓解，但可测量残留病灶（MRD）是早期复发的最强预测因素。恶性浆细胞与免疫亚群的代谢可塑性正成为MRD的关键决定因素，可能促成移植结局的差异。然而，区分MRD+与MRD-患者的代谢程序仍知之甚少。作为一种烷化剂，HDM诱导氧化应激和DNA损伤，选择出具有增强代谢特征的恶性浆细胞，同时又损害保护性T细胞亚群的重建。重要的是，种系遗传变异可能预先决定ASCT后不同的代谢命运与免疫重建。因此，我们推测MRD反映了代谢适应的MM克隆与免疫恢复受损的双重压力。我们对来自28例MM患者（进展者n=13 vs. 非进展者n=15，MRD阳性n=17 vs. MRD阴性n=11）的CD138-骨髓穿刺物进行了配对的5′ scRNA-seq和TCR-seq回顾性分析，样本采集于ASCT前后。MRD状态独立于疾病进展。BCR分析揭示浆母细胞中的克隆限制模式与生化复发相符。我们使用METAflux分析B细胞通量活性，确定MRD与氧化应激相关（OR:1.62，95% CI:1.06-2.48），而进展与氧化及生物合成代谢通路的上调相关。来自MRD+进展者的浆母细胞表现出与活跃MM克隆相符的增强增殖代谢特征。T细胞区室中的进展与氧化磷酸化强烈相关（OR:2.46，95% CI:1.44-4.20），而与MRD无显著关联。然而，MRD+进展者在CD8+ T细胞中表现出克隆限制模式，提示免疫重建缺陷。本研究识别出区分ASCT后MRD阳性与MRD阴性患者的细胞类型特异性代谢改变。B细胞中抗氧化代谢的富集，加之T细胞代谢与恢复的改变，揭示了双重脆弱性：代谢可塑性与免疫缺陷。这些结果识别出潜在的免疫代谢依赖性，可作为消除MRD并改善移植结局的治疗靶点。
查看英文原文 English abstract
In Multiple Myeloma (MM) high dose melphalan (HDM) conditioning followed by autologous stem cell transplant (ASCT) yields durable remissions, but measurable residual disease (MRD) is the strongest predictor of early relapse. Metabolic plasticity of malignant plasma cells and immune subsets are emerging as key determinants of MRD, potentially contributing to differences in transplant outcomes. However, the metabolic programs that separate MRD+ from MRD- patients remain poorly understood. As an alkylator, HDM induces oxidative stress and DNA damage that selects for malignant plasma cells with enhanced metabolic features, while simultaneously impairing reconstitution of protective T-cell subsets. Importantly, germline genetic variation may prime for distinct metabolic fates and immune reconstitution post-ASCT. Thus, we posit that MRD reflects the dual pressure of metabolically adapted MM clones and impaired immune recovery. We performed a retrospective analysis of paired 5′ scRNA-seq and TCR-seq from CD138- bone marrow aspirates of 28 MM patients (progressors n=13 vs. non-progressors n=15 and MRD-positive n=17 vs. MRD-negative n=11) collected pre- and post-ASCT. MRD status was independent of progression. BCR analysis revealed clonal restriction patterns in plasmablasts consistent with biochemical relapse. We used METAflux to analyze B-cell flux activities and determined that MRD is correlated with oxidative stress (OR:1.62, 95% CI:1.06-2.48), while progression was linked to upregulation of oxidative and biosynthetic metabolism pathways. Plasmablasts from MRD+ progressors exhibited enhanced proliferative metabolism signatures consistent with active MM clones. Progression in the T cell compartment was strongly linked to oxidative phosphorylation (OR:2.46, 95% CI:1.44-4.20), while there were no significant MRD associations. However, MRD+ progressors displayed clonal restriction patterns in CD8+ T cells signifying defective immune reconstitution. This study identifies cell-type specific metabolic alterations distinguishing MRD-positive from MRD-negative patients post-ASCT. Enrichment of antioxidant metabolism in B-cells coupled with altered T-cell metabolism and recovery demonstrates dual vulnerabilities: metabolic plasticity and immune deficits. These results identify potential immunometabolic dependencies that may serve as therapeutic targets that can be used to eliminate MRD and improve transplant outcomes.
利益披露 Disclosure
Q. Hooker, None..
T. Triche, None.