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

IF 9.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2024-12-18 DOI:10.1073/pnas.2412070121

Heng Wang, Fang Xu, Chenlu Yao, Huaxing Dai, Jialu Xu, Bingbing Wu, Bo Tian, Xiaolin Shi, Chao Wang

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引用次数: 0

Abstract

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.

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通过抑制 IDO 活性和重编程 CD8+ T 细胞反应，将细菌工程用于癌症免疫疗法

近年来，抑制吲哚胺2,3双加氧酶（IDO）用于抗癌治疗已引起广泛关注。然而，目前的IDO抑制剂面临着限制其临床应用的重大挑战。在这里，我们通过基因工程改造了一种高色氨酸表达的丁酸梭菌（L-Trp CB）菌株，该菌株可以在严格的全身给药后定植肿瘤。我们发现L-Trp CB产生的丁酸盐可以抑制IDO活性，阻止肿瘤中色氨酸的分解代谢和犬尿氨酸的积累。此外，L-Trp CB释放的大量色氨酸可以提供离散信号，支持肿瘤微环境内CD8+ T细胞的激活和能量代谢。我们观察到L-Trp CB显著恢复CD8+ T细胞的比例和功能，导致小鼠和家兔多发性肿瘤模型中肿瘤生长明显延迟，副作用有限。我们在此提供了一种合成生物学治疗策略，通过抑制IDO活性和重编程肿瘤中的CD8+ T细胞反应来增强肿瘤免疫治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.