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.
Authors
- Stephany Y. Tzeng (ORCID: https://orcid.org/0000-0002-7561-482X)
- Betty Tyler (ORCID: https://orcid.org/0000-0001-9800-6969)
- Michael Lim (ORCID: https://orcid.org/0000-0003-0523-3076)
- Maria Bederson (ORCID: https://orcid.org/0000-0002-3790-5271)
- Ravi Medikonda
- Christopher M. Jackson (ORCID: https://orcid.org/0000-0002-5958-2004)
- Caren Yu-Ju Wu (ORCID: https://orcid.org/0000-0003-3989-2117)
- John Choi (ORCID: https://orcid.org/0000-0002-5162-5903)
- Kwang Bog Cho (ORCID: https://orcid.org/0000-0003-1776-734X)
- Henry Brem (ORCID: https://orcid.org/0000-0001-7539-4786)
- Liang Zhao (ORCID: https://orcid.org/0000-0002-2126-6778)
- Rohit Verma (ORCID: https://orcid.org/0009-0009-6699-1285)
- Brandon Hwa-Lin Bergsneider (ORCID: https://orcid.org/0000-0001-7013-8150)
- Drew M. Pardoll (ORCID: https://orcid.org/0000-0001-6215-1013)
- Jennifer E. Kim (ORCID: https://orcid.org/0000-0003-3604-1341)
- Lily H. Kim (ORCID: https://orcid.org/0000-0002-9272-019X)
- Eli Yazigi (ORCID: https://orcid.org/0000-0003-3537-470X)
- Si Yeon Lee
- Prajwal Rajappa (ORCID: https://orcid.org/0000-0002-5911-9554)
- Sakthi Rajendran (ORCID: https://orcid.org/0000-0002-1603-9693)
- Kisha Patel (ORCID: https://orcid.org/0000-0002-0866-6195)
- Laura Saleh
- Crystal L. Mackall (ORCID: https://orcid.org/0000-0003-0359-9023)
- Ayush Pant (ORCID: https://orcid.org/0000-0003-3231-2917)
- Yiyun Chen (ORCID: https://orcid.org/0000-0003-3886-2100)
- William Lee Wang (ORCID: https://orcid.org/0000-0002-3121-2415)
- Gordon Li (ORCID: https://orcid.org/0000-0001-8372-0676)
- Ryan T. Nitta (ORCID: https://orcid.org/0000-0002-4204-6985)
- Aanchal Jain (ORCID: https://orcid.org/0009-0007-5483-9900)
Institutions
- Nationwide Children's Hospital (US)
- Johns Hopkins University (US)
- Palo Alto University (US)
- Johns Hopkins Medicine (US)
- The Ohio State University Wexner Medical Center (US)
- Complete Omics (United States) (US)
- Stanford Medicine (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- Stanford University (US)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2024-08-12
- DOI
- https://doi.org/10.1158/2326-6066.cir-24-0230
- Citations
- 14
- Primary Topic
- Chemokine receptors and signaling
- Type
- article
- Field-Weighted Citation Impact
- 3.96
Funders
- National Institute of General Medical Sciences