肿瘤细胞治疗研究
英文原题：Dendritic Cell Dysfunction Underlies Immune Escape After Adoptive Cellular Therapy in Glioblastoma.
背景/目的：胶质母细胞瘤（GBM）仍是一种致死性原发性中枢神经系统恶性肿瘤，对免疫治疗反应有限。
背景/目的：胶质母细胞瘤（GBM）仍是一种致死性原发性CNS恶性肿瘤，对免疫治疗反应有限。过继性细胞治疗（ACT）在临床前模型中可改善生存，但肿瘤最终仍会复发。虽然T细胞耗竭是耐药的一种常见机制，但树突状细胞（DC）功能障碍的贡献仍不清楚。我们旨在明确ACT后免疫逃逸的机制，重点关注DC功能以及缺氧的作用。方法：使用小鼠胶质瘤模型（KR158B-luc），小鼠接受由肿瘤RNA脉冲DC疫苗和过继转移T细胞组成的ACT治疗。通过流式细胞术分析肿瘤浸润免疫细胞群。使用T细胞活化试验评估DC功能。对分选后的DC进行bulk RNA测序和基因集富集分析。在体外模拟缺氧，并使用CRISPR介导的敲除扰动HIF1α。结果：ACT显著提高了生存，但未阻止肿瘤复发。逃逸的肿瘤含有大量细胞毒性、非耗竭T细胞，表明在ACT下T细胞功能障碍并非复发的主要驱动因素。相反，肿瘤相关DC尽管抗原摄取保留，却表现出T细胞活化受损。转录组分析显示抗原呈递和共刺激信号减少，同时耐受性因子表达增加。ACT治疗的肿瘤表现出缺氧通路激活增强，DC中HIF1α表达升高。缺氧诱导DC耐受性程序并降低其活化T细胞的能力，而破坏HIF1α可部分逆转这一效应。ACT后免疫浸润和炎症增加进一步放大了缺氧信号并增强了DC耐受。结论：DC功能障碍是胶质瘤ACT后免疫逃逸的关键机制之一。缺氧驱动的DC耐受化损害了持续性抗肿瘤免疫，凸显缺氧-DC轴作为增强免疫治疗疗效的有前景的治疗靶点。
Background/Objectives : Glioblastoma (GBM) remains a lethal primary CNS malignancy with limited response to immunotherapy. Adoptive cellular therapy (ACT) improves survival in preclinical models, yet tumors ultimately recur. While T cell exhaustion is a common mechanism of resistance, the contribution of dendritic cell (DC) dysfunction remains unclear. We aimed to define mechanisms of immune escape following ACT, focusing on DC function and the role of hypoxia. Methods : Using a murine glioma model (KR158B-luc), mice were treated with ACT consisting of tumor RNA-pulsed DC vaccines and adoptively transferred T cells. Tumor-infiltrating immune populations were analyzed by flow cytometry. DC function was assessed using T cell activation assays. Bulk RNA sequencing and gene set enrichment analysis were performed on sorted DCs. Hypoxia was modeled in vitro, and HIF1α was perturbed using CRISPR-mediated knock-out. Results : ACT significantly increased survival but did not prevent tumor recurrence. Escaped tumors contained abundant cytotoxic, non-exhausted T cells, indicating that T cell dysfunction was not the primary driver of recurrence under ACT. Instead, tumor-associated DCs exhibited impaired T cell activation despite preserved antigen uptake. Transcriptomic analyses revealed reduced antigen presentation and co-stimulatory signaling, alongside increased expression of tolerogenic factors. ACT-treated tumors demonstrated heightened hypoxia pathway activation, with elevated HIF1α expression in DCs. Hypoxia induced DC tolerogenic programs and reduced their ability to activate T cells, an effect partially reversed by HIF1α disruption. Increased immune infiltration and inflammation following ACT further amplified hypoxia signaling and enhanced DC tolerance. Conclusions : DC dysfunction is one of the key mechanisms of immune escape following ACT in glioma. Hypoxia-driven tolerization of DCs impairs sustained anti-tumor immunity, highlighting the hypoxia-DC axis as a promising therapeutic target to enhance immunotherapy efficacy.
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