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
B7-H4 对胶质瘤中 CD8⁺ T 细胞浸润的减少及其抗肿瘤功能障碍的诱导
英文原题：B7-H4 reduces the infiltration of CD8+T cells and induces their anti-tumor dysfunction in gliomas.
查看英文原题
B7-H4 reduces the infiltration of CD8+T cells and induces their anti-tumor dysfunction in gliomas.
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中文摘要
B7-H4 是肿瘤免疫治疗中一种有前景的免疫检查点分子。我们此前研究显示，胶质瘤患者 B7-H4 高表达与TIL（肿瘤浸润淋巴细胞）缺乏密切相关。
在此基础上，本研究考察 B7-H4 对胶质瘤 CD8+ TIL 的影响及相关分子机制。采用胶质瘤队列中 129 份 B7-H4 阳性肿瘤样本，通过免疫组织化学评估 B7-H4 表达和 CD8+ TIL 定量。将 5 例胶质瘤患者的 CD8+ TIL 与 B7-H4 蛋白共培养，通过流式细胞术和 ELISpot 评估其抗肿瘤功能障碍。采用原位小鼠胶质瘤模型，通过免疫组织化学和流式细胞术研究 B7-H4 对胶质瘤 CD8+ TIL 的作用。将患者来源 CD8+ TIL 与 B7-H4 蛋白共培养后，采用 RNA 测序和蛋白质印迹探究潜在分子机制。
结果显示，在患者队列（P < 0.05）和原位小鼠模型（P < 0.01）中，胶质瘤 CD8+ TIL 密度均与 B7-H4 表达负相关。B7-H4 还降低胶质瘤 CD8+ TIL 中 CD137 和 CD103 的表达（两者均 P < 0.05），并以剂量依赖方式减少抗肿瘤细胞因子 IFN-γ 和 TNF-α 的分泌（两者均 P < 0.01）。
此外，B7-H4 可通过下调 AKT 和 eNOS 的磷酸化，诱导胶质瘤 CD8+ TIL 早期功能障碍（两者均 P < 0.05）。
总之，B7-H4 减少胶质瘤 CD8+ TIL 浸润，并诱导抗肿瘤功能障碍表型；其还可能通过 AKT-eNOS 通路损害这些 TIL 的抗肿瘤功能。研究结果提示 B7-H4 可作为未来胶质瘤免疫治疗的潜在靶点。
展开英文摘要原文
B7-H4 is a promising immune checkpoint molecule in tumor immunotherapy.
Our previous study showed that high B7-H4 expression was strongly correlated with deficiency in tumor infiltrated lymphocytes (TILs) in glioma patients. On this basis, we investigated the impact of B7-H4 on CD8+TILs in gliomas and the associated molecular mechanism here. B7-H4-positive tumor samples (n=129) from our glioma cohort were used to assess B7-H4 expression and CD8+TIL quantification by immunohistochemistry.
CD8+TILs from five glioma patients cultured with B7-H4 protein were used to evaluate anti-tumor dysfunction by flow cytometry and ELISpot. An orthotopic murine glioma model was used to investigate the role of B7-H4 in glioma CD8+TILs by immunohisto- chemistry and flow cytometry. CD8+TILs from glioma patients cultured with B7-H4 protein were used to explore the potential molecular mechanism by RNA sequencing and western blot.
Our results showed that glioma CD8+TIL density was negatively correlated with B7-H4 expression both in glioma patient cohort (P < 0. 05) and orthotopic glioma murine model (P < 0. 01). B7-H4 also lowered the expression of CD137 and CD103 (P < 0. 05 for both) in glioma CD8+TILs and reduced their secretion of the anti-tumor cytokines IFN- and TNF- (P < 0. 01 for both) in a dose-dependent manner.
Furthermore, B7-H4 was found to induce early dysfunction of glioma CD8+TILs by downregulating the phosphorylation of AKT and eNOS (P < 0. 05 for both).
In conclusion, B7-H4 reduced the infiltration of glioma CD8+TILs and induced an anti-tumor dysfunction phenotype. B7-H4 may also impair the anti-tumor function of glioma CD8+TILs via the AKT-eNOS pathway. These results indicated that B7-H4 may serve as a potential target in future glioma immunotherapy.
论文信息
- 作者
- Qi Y、Hu L、Ji C、Yang X、Yao J、Chen D、Yao Y
- 第一作者单位
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China; Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China.China
- 通讯作者单位
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China; Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China. Electronic address: yu_yao@fudan.edu.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Neoplasia (New York, N.Y.)2024 Aug
- 原文标识
- PubMed 38796932 · DOI 10.1016/j.neo.2024.101007
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