Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+T cell response

• 成果类型: Article
• 署名作者: Wang, Heng; Xu, Fang; Yao, Chenlu; Dai, Huaxing; Xu, Jialu; Wu, Bingbing; Tian, Bo; Shi, Xiaolin; Wang, Chao
• 署名单位: Soochow University - China; Soochow University - China; Soochow University - China
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13404
• DOI: 10.1073/pnas.2412070121
• 发表日期: 2024-12-24
• 关键词: amino-acid-transport; t-cell; tryptophan-metabolism; differentiation; target; mtor

摘要

Inhibiting indoleamine 2,3 dioxygenase (IDO) for anticancer therapy has garnered significant attention in recent years. However, current IDO inhibitors face significant challenges which limit their clinical application. Here, we genetically engineered a high tryptophan- expressing Clostridium butyricum (L- Trp CB) strain that can colonize tumors strictly following systemic administration. We revealed that butyrate produced by L- Trp CB can inhibit IDO activity, preventing tryptophan catabolism and kynurenine accumulation in tumors. In addition, the large released tryptophan by L- Trp CB can provide discrete signals that support CD8+ T cell activation and energy metabolism within the tumor microenvironment. We observed that L- Trp CB significantly restored the proportion and function of CD8+ T cells, leading to significantly delayed tumor growth in both mouse and rabbit multiple tumor models with limited side effects. We here provide a synthetic biology treatment strategy for enhanced tumor immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response in tumors.