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
CCR6-CCL20 轴促进肿瘤中调节性 T 细胞糖酵解和免疫抑制
英文原题：The CCR6-CCL20 Axis Promotes Regulatory T-cell Glycolysis and Immunosuppression in Tumors.
查看英文原题
The CCR6-CCL20 Axis Promotes Regulatory T-cell Glycolysis and Immunosuppression in Tumors.
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中文摘要
调节性T细胞（Treg）是肿瘤微环境中的重要参与者。然而，其免疫抑制效应背后的机制尚不清楚。我们发现，肿瘤浸润Treg中CCR6-CCL20活性与更高的糖酵解活性相关，而Ccr6的缺失降低了糖酵解和乳酸产生，同时增加了代偿性谷氨酰胺代谢。由于活化诱导的糖酵解减少，Ccr6-/- Treg对CD8+ T细胞的免疫抑制活性被消除。此外，与野生型小鼠相比，Ccr6-/-小鼠在多种肿瘤模型中表现出改善的生存率，而Treg和CD8+ T细胞清除消除了这种改善。此外，在临床前胶质瘤模型中，Ccr6缺失进一步促进了抗PD-1治疗的疗效。随后使用siRNA敲低Ccl20也证明了抗肿瘤疗效的改善。我们的结果揭示了CCR6作为Treg诱导免疫抑制的标志物和调节因子，并确定了靶向Treg免疫抑制活性代谢决定因素的方法。
展开英文摘要原文
Regulatory T cells (Treg) are important players in the tumor microenvironment.
However, the mechanisms behind their immunosuppressive effects are poorly understood.
We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity toward CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis.
Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wild-type mice and Treg and CD8+ T-cell depletion abrogated the improvement.
In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy.
Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.
论文信息
- 作者
- Pant A、Jain A、Chen Y、Patel K、Saleh L、Tzeng S、Nitta RT、Zhao L
- 单位
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.United States
- 文献类型
- 非美国政府资助研究
- 期刊
- Cancer immunology research2024 Nov 4
- 原文标识
- PubMed 39133127 · DOI 10.1158/2326-6066.CIR-24-0230