PO.CL05.04 · 临床研究
PD-1治疗无应答者在黑色素瘤中共享一个OXPHOS与神经元样耐药联合程序
Nonresponders to PD-1 therapy share a combined OXPHOS and neuronal-like resistance program in melanoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：靶向PD-1的免疫检查点抑制剂（ICI）已彻底改变了黑色素瘤的治疗，但仅有一部分患者获得持久获益。应答性背后的分子程序仍未完全阐明。我们旨在通过聚焦于与转化的癌症特征特异性相关的改变，鉴定区分应答者与无应答者的基因表达模式。
方法：我们汇编了来自17项独立研究的治疗前转录谱，合并了551例黑色素瘤患者的数据，其中包括233例抗PD-1治疗应答者。ROC分析评估了单个基因的判别潜力。鉴定出在应答者和无应答者中均具有高AUC和表达值的基因。使用cancerhallmarks.com评估特征富集，并进行基因本体分析以表征潜在的生物学程序。显著性差异基于倍数变化≥1.4和p<0.05。
结果：在应答者中，467个过表达基因揭示出高度协调的免疫炎症状态，富集了Fc-γ受体信号（p = 3.97×10⁻⁸²）、经典补体激活（p = 1.42×10⁻⁸¹）以及T细胞和B细胞受体信号（p = 3.47×10⁻⁴，3.06×10⁻⁴）。GO术语突出了T细胞活化、淋巴细胞介导的免疫和强烈的IFN-γ应答。癌症特征富集分析将“逃避免疫破坏”鉴定为唯一显著的特征（p < 0.0001），强调临床获益源于预先存在的免疫激活微环境，而非肿瘤内在程序，如增殖、代谢重编程或分化状态。无应答者中的685个过表达基因汇聚为代谢扩增和谱系重编程的肿瘤状态。Reactome分析揭示了线粒体程序的强烈上调，包括线粒体RNA加工（p = 1.47×10⁻¹²）和呼吸电子传递（p = 2.92×10⁻²），定义了一种可抑制抗肿瘤免疫的高OXPHOS表型。与髓鞘形成、少突胶质细胞分化和跨突触信号相关的补充GO术语突出了一种与抗原呈递减少和T细胞排斥相关的神经元样去分化程序，构成了免疫识别的多层屏障。
结论：ICI无应答者一贯表现出高OXPHOS代谢和神经元样去分化，导致免疫沉默。这两种耐药程序在多个独立队列中的共存揭示了对PD-1应答的联合转录屏障。
查看英文原文 English abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting PD-1 have transformed melanoma therapy, yet only a subset of patients derive durable benefit. The molecular programs underlying responsiveness remain incompletely defined. We aimed to identify gene-expression patterns that distinguish responders from nonresponders by focusing on alterations specifically related to transformed cancer hallmarks.
METHODS: We compiled pretreatment transcriptional profiles from 17 independent studies, pooling data for 551 melanoma patients, including 233 responders to anti-PD-1 therapy. ROC analyses evaluated the discriminative potential of individual genes. Genes with high AUC and expression values in both responders and nonresponders were identified. Hallmark enrichment was assessed using cancerhallmarks.com, and gene ontology analyses were conducted to characterize the underlying biological programs. Significant differences were based on a fold change ≥ 1.4 and a p<0.05.
RESULTS: In responders, 467 overexpressed genes revealed a highly coordinated immune-inflamed state, with enriched Fc-gamma receptor signaling (p = 3.97×10⁻⁸²), classical complement activation (p = 1.42×10⁻⁸¹), and T- and B-cell receptor signaling (p = 3.47×10⁻⁴, 3.06×10⁻⁴). GO terms highlighted T-cell activation, lymphocyte-mediated immunity, and a strong IFN-gamma response. Cancer hallmark enrichment analysis identified “Evasion of Immune Destruction” as the only significant hallmark (p < 0.0001), emphasizing that clinical benefit arises from a pre-existing immune-activated microenvironment rather than tumor-intrinsic programs, such as proliferation, metabolic rewiring, or differentiation state. The 685 overexpressed genes in nonresponders converged on a metabolically amplified and lineage-rewired tumor state. Reactome analysis revealed a strong upregulation of mitochondrial programs, including mitochondrial RNA processing (p = 1.47 × 10⁻¹²) and respiratory electron transport (p = 2.92 × 10⁻²), defining a high-OXPHOS phenotype that can suppress antitumor immunity. Complementary GO terms related to myelination, oligodendrocyte differentiation, and trans-synaptic signaling highlighted a neuronal-like dedifferentiation program linked to reduced antigen presentation and T-cell exclusion, creating a multilayered barrier to immune recognition.
CONCLUSION: ICI nonresponders consistently exhibit high-OXPHOS metabolism and neuronal-like dedifferentiation, resulting in immune silence. The co-occurrence of these two resistance programs across multiple independent cohorts reveals a combined transcriptional barrier to PD-1 response.
利益披露 Disclosure
O. Menyhart, None..
J. Fekete, None..
B. Gyorffy, None.