Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Stanford Cancer Institute, Stanford School of Medicine, Stanford, California.
Cancer Immunol Res. 2024 Nov 4;12(11):1542-1558. doi: 10.1158/2326-6066.CIR-24-0230.
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.
调节性 T 细胞（Treg）是肿瘤微环境中的重要参与者。然而，其免疫抑制作用的机制仍不清楚。我们发现，肿瘤浸润性 Treg 中的 CCR6-CCL20 活性与更高的糖酵解活性有关，而 Ccr6 的缺失则减少了糖酵解和乳酸的产生，同时增加了代偿性谷氨酰胺代谢。由于激活诱导的糖酵解减少，Ccr6-/-Treg 对 CD8+T 细胞的免疫抑制活性被削弱。此外，与野生型小鼠相比，Ccr6-/-小鼠在多种肿瘤模型中表现出更好的存活率，而 Treg 和 CD8+T 细胞的耗竭则消除了这种改善。此外，Ccr6 的缺失进一步促进了抗 PD-1 治疗在临床前脑胶质瘤模型中的疗效。用 siRNA 进行的后续 Ccl20 敲低也证明了抗肿瘤疗效的改善。我们的研究结果揭示了 CCR6 作为 Treg 诱导的免疫抑制的标志物和调节剂，并确定了针对 Treg 免疫抑制活性的代谢决定因素的靶向方法。
