Cross-Disease myeloid remodeling along the GMP–TAM axis predicts immunotherapy response in glioma

IF 3.2 4区医学 Q3 NEUROSCIENCES

Brain Research Pub Date : 2026-02-01 Epub Date: 2025-11-30 DOI:10.1016/j.brainres.2025.150083

Yuanyuan Zhang , Xin Liu , Shi Hua

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Abstract

Backgrounds

Immune checkpoint inhibitor-induced colitis (CICs) represents a state of systemic immune activation and is paradoxically associated with superior anti-tumor responses. This study has been designed to explore gene signatures derived from CICs that could identify the key immunological drivers, and predict sensitivity of immunotherapy in immunologically cold tumors e.g. glioma. Methods: We integrated bulk, single-cell, and spatial transcriptomic data from CICs and glioma cohorts. Cross-disease analysis have been performed to identify an immunotherapy-responsive granulocyte-monocyte progenitor (IR-GMP) signature. Risk score (RS) model has been constructed through LASSO regression, and have been validated for its potential prognostic as well as predictive values. Results: We have identified 112 IR-GMP genes enriched in pathways that may cause myeloid immunosuppression. A four-gene RS model (RAC2, LAPTM5, HCLS1, CD74) has been developed, and glioma patients have been divided into high- and low-risk groups based on the model. RS is an independent prognostic factor, and demonstrated to exhibit superior accuracy for predicting survival when combining with clinical variables. High-RS tumors exhibited immunosuppressive TME characterized by M2 macrophage enrichment, SPP1-signaling hyperactivation, and an immune-tolerant genomic landscape (C4 subtype). Crucially, the high-RS group showed significantly higher immunophenoscores under PD-1 and combined PD-1/CTLA-4 blockade, indicating potential sensitivity to immunotherapy, and distinct chemotherapy susceptibility. Single-cell and spatial transcriptomic results confirmed the lineage specificity and regional colocalization of RS genes with M2 macrophages. Conclusions: Our cross-disease analysis unveils a conserved GMP–TAM myeloid remodeling axis in glioma. The derived RS model may serve as a powerful marker for predicting prognosis, and also for predicting the benefits derived from immunotherapy, offering a novel tool for precision immunotherapy in glioma.

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沿GMP-TAM轴的跨疾病骨髓重塑预测胶质瘤的免疫治疗反应。

背景：免疫检查点抑制剂诱导的结肠炎（CICs）代表了一种全身性免疫激活状态，并且矛盾地与优越的抗肿瘤反应相关。本研究旨在探索来自CICs的基因特征，这些特征可以识别关键的免疫驱动因素，并预测免疫治疗对免疫冷肿瘤（如胶质瘤）的敏感性。方法：我们整合了来自CICs和胶质瘤队列的大量、单细胞和空间转录组数据。已经进行了跨疾病分析，以确定免疫治疗反应性粒细胞-单核细胞祖细胞（IR-GMP）特征。通过LASSO回归构建了风险评分（RS）模型，并对其潜在的预后和预测价值进行了验证。结果：我们已经鉴定出112个富集于髓细胞免疫抑制通路的IR-GMP基因。建立了四基因RS模型（RAC2、LAPTM5、HCLS1、CD74），并根据模型将胶质瘤患者分为高危组和低危组。RS是一个独立的预后因素，当与临床变量相结合时，RS在预测生存方面表现出更高的准确性。高rs肿瘤表现出免疫抑制TME，其特征是M2巨噬细胞富集、spp1信号过度激活和免疫耐受基因组景观（C4亚型）。至关重要的是，高rs组在PD-1和PD-1/CTLA-4联合阻断下显示出显著更高的免疫表型，表明对免疫治疗的潜在敏感性和明显的化疗敏感性。单细胞和空间转录组学结果证实了RS基因与M2巨噬细胞的谱系特异性和区域共定位。结论：我们的跨疾病分析揭示了胶质瘤中保守的GMP-TAM髓系重塑轴。所建立的RS模型可作为预测预后的有力指标，也可用于预测免疫治疗的获益，为胶质瘤的精确免疫治疗提供了新的工具。

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来源期刊

Brain Research 医学-神经科学

CiteScore

5.90

自引率

3.40%

发文量

268

审稿时长

47 days

期刊介绍： An international multidisciplinary journal devoted to fundamental research in the brain sciences. Brain Research publishes papers reporting interdisciplinary investigations of nervous system structure and function that are of general interest to the international community of neuroscientists. As is evident from the journals name, its scope is broad, ranging from cellular and molecular studies through systems neuroscience, cognition and disease. Invited reviews are also published; suggestions for and inquiries about potential reviews are welcomed. With the appearance of the final issue of the 2011 subscription, Vol. 67/1-2 (24 June 2011), Brain Research Reviews has ceased publication as a distinct journal separate from Brain Research. Review articles accepted for Brain Research are now published in that journal.