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

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Ayush 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
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引用次数: 0

Abstract

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.

CCR6-CCL20轴促进肿瘤中调节性T细胞的糖酵解和免疫抑制。
调节性 T 细胞(Tregs)是肿瘤微环境中的重要角色。然而,人们对其免疫抑制作用背后的机制却知之甚少。我们发现,肿瘤浸润Tregs中的CCR6-CCL20活性与更强的糖酵解活性有关,消减Ccr6可减少糖酵解和乳酸的产生,同时增加谷氨酰胺的代偿性代谢。由于活化诱导的糖酵解减少,Ccr6-/-Tregs 对 CD8+ T 细胞的免疫抑制活性减弱。此外,与野生型小鼠相比,Ccr6-/-小鼠在多种肿瘤模型中的存活率都有所提高,而Treg和CD8+ T细胞耗竭则会使存活率降低。此外,在临床前胶质瘤模型中,Ccr6消融进一步促进了抗PD-1疗法的疗效。后续的 siRNA 敲除 Ccl20 也显示了抗肿瘤疗效的改善。我们的研究结果揭示了 CCR6 是 Treg 诱导的免疫抑制的标记物和调节因子,并确定了针对 Treg 免疫抑制活性的代谢决定因素的方法。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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