posted on 2024-11-04, 08:23authored byAyush Pant, Aanchal Jain, Yiyun Chen, Kisha Patel, Laura Saleh, Stephany Tzeng, Ryan T. Nitta, Liang Zhao, Caren Yu-Ju Wu, Maria Bederson, William Lee Wang, Brandon Hwa-Lin Bergsneider, John Choi, Ravi Medikonda, Rohit Verma, Kwang Bog Cho, Lily H. Kim, Jennifer E. Kim, Eli Yazigi, Si Yeon Lee, Sakthi Rajendran, Prajwal Rajappa, Crystal L. Mackall, Gordon Li, Betty Tyler, Henry Brem, Drew M. Pardoll, Michael Lim, Christopher M. Jackson
Figure S2: CCR6 expression is enhanced in tumor-infiltrating Tregs co-expressing checkpoints and Ccr6 ablation reduces immunosuppressive phenotype.
Funding
National Institute of General Medical Sciences (NIGMS)
United States Department of Health and Human Services
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.