The CCR6–CCL20 Axis Promotes Regulatory T-cell Glycolysis and Immunosuppression in Tumors

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.