CD81 通过阻断 CD274/PD-L1 的选择性自噬降解驱动放射抵抗性胶质母细胞瘤的免疫逃逸
CD81 drives immune evasion in radioresistant glioblastoma by blocking selective autophagic degradation of CD274/PD-L1.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
一项外科窗口机会试验，评估 PCSK9 抑制剂 evolocumab 对胶质瘤中肿瘤 MHC-I 表达和 CD8(+) 浸润的影响
英文原题：A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8(+) infiltration in glioma.
查看英文原题
A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8(+) infiltration in glioma.
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中文摘要
许多癌症通过下调表面主要组织相容性复合体（MHC）-I来逃避免疫监视。前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）促进MHC-I降解，并且在胶质瘤中升高。Evolocumab是一种临床批准的PCSK9抑制剂，在临床前癌症模型中可恢复MHC-I表达。
然而，单克隆抗体的血脑/肿瘤屏障穿透性（BBB/BTB）有限。我们进行了一项机会窗试验，评估evolocumab的BBB/BTB穿透性和生物学效应（PesKE；NCT04937413）。纳入接受临床指征活检或切除的新诊断或复发胶质瘤患者（n = 32，M：16，F：16；对照平均年龄：51.85，evolocumab：53）。干预参与者（n = 6）在操作前接受单次皮下evolocumab剂量，其中4例提供了研究组织。未观察到显著不良事件。在所有分析干预组织中均检测到evolocumab，平均肿瘤:血液比值为0.0222（SD ± 0.0190），与其他单克隆抗体相似。Evolocumab定量在对比增强病例（平均0.0068 fmol/mcg（SD ± 0.001））中比非对比增强病例（平均0.0015 fmol/mcg（SD ± 0.0004））高4.44倍。
蛋白质组学分析发现evolocumab与MHC-I亚型（HLA-A-C，E-G）之间呈正趋势，与HLA-H显著正相关（R 2 = 0.9584，p = 0.021*）。evolocumab滴度较高的肿瘤组织显示表面MHC-I和CD8 + T细胞浸润增加。与低滴度组织和未治疗对照相比，高滴度组织中观察到CD8 + TNF、FASLG和GZMA转录增加。切除前evolocumab耐受性良好，但表现出与其他单克隆抗体相似的BBB/BTB穿透性。肿瘤内evolocumab/PCSK9i增加可能增强肿瘤MHC-I/效应CD8+浸润。未来工作将探索将evolocumab与BBB/BTB开放疗法如低强度聚焦超声联合使用。
展开英文摘要原文
Many cancers evade immunosurveillance by downregulating surface major histocompatibility class (MHC)-I. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes MHC-I degradation and is elevated in glioma. Evolocumab is a clinically approved PCSK9 inhibitor which restores MHC-I expression in pre-clinical cancer models.
However, monoclonal antibodies have limited blood brain/tumor barrier penetrance (BBB/BTB).
We conducted a window-of-opportunity trial, evaluating evolocumab's BBB/BTB penetrance and biological effect (PesKE; NCT04937413). Patients with newly diagnosed or recurrent glioma undergoing a clinically indicated biopsy or resection were enrolled (n = 32, M: 16, F: 16; control average age: 51. 85, evolocumab: 53). Intervention participants (n = 6) received a single subcutaneous evolocumab dose pre-procedure, of which 4 provided research tissue. No significant adverse events were observed. Evolocumab was detected in all analyzed intervention tissue, with an average tumor: blood ratio of 0. 0222 (SD ± 0. 0190), akin to other monoclonals. Evolocumab quantitation was 4. 44× greater in contrast-enhancing (mean 0. 0068 fmol/mcg (SD ± 0. 001)) vs non-contrast enhancing cases (mean 0.
0015 fmol/mcg (SD ± 0. 0004)). Proteomic analysis found positive trends between evolocumab and MHC-I subtypes (HLA-A-C, E-G), with a significant positive correlation with HLA-H (R 2 = 0. 9584, p = 0. 021*). Tumor tissue with higher evolocumab titers demonstrated increased surface MHC-I and CD8 + T cell infiltration. Increased CD8 + TNF, FASLG and GZMA transcription was observed in high titer tissue compared to low titer tissue and untreated controls.
Pre-resection evolocumab is well tolerated but exhibits BBB/BTB penetrance akin to other monoclonal antibodies. Increased tumoral evolocumab/PCSK9i may enhance tumoral MHC-I/effector CD8 + infiltration. Future work will explore combining evolocumab with BBB/BTB opening therapies like low-intensity focused ultrasound.
论文信息
- 作者
- Singh K、Foster MW、Violette MJ、Corcoran AM、Hotchkiss KM、Railton CO、Blandford EE、Blethen KE
- 第一作者单位
- The Preston Robert Tisch Brain Tumor Center, Duke University, Box 3624, Durham, NC, 27710, USA.United States
- 通讯作者单位
- The Preston Robert Tisch Brain Tumor Center, Duke University, Box 3624, Durham, NC, 27710, USA. mustafa.khasraw@duke.edu.United States
- 文献类型
- I 期临床试验
- 期刊
- Scientific reports2025 Oct 23
- 原文标识
- PubMed 41131134 · DOI 10.1038/s41598-025-21064-9
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