PO.TB10.04 · 肿瘤生物学
与NSCLC检查点阻断应答相关的前体耗竭型CD8⁺ T细胞的转录程序
Transcriptional programs of precursor-exhausted CD8⁺ T cells associated with checkpoint blockade response in NSCLC
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摘要 Abstract
中文摘要
免疫检查点阻断（ICB）仅使部分非小细胞肺癌（NSCLC）患者获益，而主要病理缓解（MPR）的免疫决定因素仍未完全明确。近期研究提示，前体耗竭型CD8⁺ T细胞（Tpex）对于维持抗肿瘤免疫及生成被PD-1阻断重新激活的效应细胞池至关重要。尽管Tpex细胞往往在应答者中富集，但其促成疗效改善的机制仍不清楚。在本研究中，我们利用一个公开可用的单细胞RNA测序数据集（GSE243013），分析了MPR患者与非应答者的Tpex转录状态。差异基因表达分析显示，应答者的Tpex细胞表现出参与金属离子稳态（如MT2A）和适应性应激耐受（如MTRNR2L12、SLPI、ITGA6）的基因表达上调。相反，非应答者的Tpex细胞优先表达干扰素刺激及增殖应激程序（如TYMS、HMOX1、LINC01480）。通路富集分析支持了这些发现，在应答者中识别出金属硫蛋白相关过程，在非应答者中识别出富集的细胞因子/干扰素信号传导。对Tpex差异表达基因的Cox比例风险回归建模进一步表明，在非应答者中上调的MYB原癌基因样2（MYBL2）与较差的无复发生存相关（HR≈1.28；95% CI: 1.12-1.44；校正后P = 0.016）。与增殖或干扰素驱动的功能失调相关的其他基因（RRM2、GEM、PKMYT1、ISG15）与不良结局呈现名义上的关联，进一步印证了在经历复发的患者中存在向终末耗竭转变的循环、IFN高表达状态。综上所述，我们的研究为将Tpex功能状态与治疗应答和疾病复发相联系提供了重要信息，对完善NSCLC免疫治疗策略具有潜在意义。研究使用了生成式AI辅助，且仅限于改善方法学描述的清晰度。
查看英文原文 English abstract
Immune checkpoint blockade (ICB) benefits only a subset of patients with non-small cell lung cancer (NSCLC), and the immune determinants of major pathologic response (MPR) remain incompletely defined. Recent studies suggest that precursor-exhausted CD8⁺ T cells (Tpex) are critical for sustaining anti-tumor immunity and generating the effector pool reinvigorated by PD-1 blockade. Although Tpex cells tend to be enriched in responders, the mechanisms by which they contribute to improved therapeutic outcomes remain unclear. In this study, we profiled Tpex transcriptional states in patients with MPR versus non-responders using a publicly available single-cell RNA-sequencing dataset (GSE243013). Differential gene expression analysis revealed that Tpex cells from responders showed upregulated expression of genes involved in metal-ion homeostasis (e.g., MT2A) and adaptive stress tolerance (e.g., MTRNR2L12, SLPI, ITGA6). In contrast, Tpex cells from non-responders preferentially expressed interferon-stimulated and proliferative-stress programs (e.g., TYMS, HMOX1, LINC01480). Pathway enrichment analysis supported these findings, identifying metallothionein-associated processes in responders and enriched cytokine/interferon signaling in non-responders. Cox proportional hazard regression modeling of Tpex differentially expressed genes further demonstrated that MYB proto-oncogene like 2 (MYBL2), which was upregulated in non-responders, was associated with poorer recurrence-free survival (HR ≈ 1.28; 95% CI: 1.12-1.44; adjusted P = 0.016). Additional genes linked to proliferative or interferon-driven dysfunction (RRM2, GEM, PKMYT1, ISG15) showed nominal associations with adverse outcomes, reinforcing the presence of a cycling, IFN-high, shift towards terminal exhaustion in patients who experienced recurrence. Taken together, our study provides important information for linking Tpex functional states to therapeutic response and disease recurrence, with potential implications for refining immunotherapy strategies in NSCLC. Generative AI assistance was used and limited to improving clarity of methodological descriptions.
利益披露 Disclosure
E. D. Littlestone, None..
M. Ahmmad, None..
X. Zhang, None.