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.

中文翻译：

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通过抑制 IDO 活性和重编程 CD8+ T 细胞反应来改造细菌用于癌症免疫治疗


近年来，抑制吲哚胺 2,3 双加氧酶 （IDO） 用于抗癌治疗引起了广泛关注。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，我们对一种高表达色氨酸的丁酸梭菌 （L-Trp CB） 菌株进行了基因工程改造，该菌株可以在全身给药后严格定植肿瘤。我们揭示了 L-Trp CB 产生的丁酸盐可以抑制 IDO 活性，防止色氨酸分解代谢和犬尿氨酸在肿瘤中的积累。此外，L-Trp CB 释放的大色氨酸可以提供离散信号，支持肿瘤微环境中的 CD8+ T 细胞活化和能量代谢。我们观察到 L-Trp CB 显着恢复了 CD8+ T 细胞的比例和功能，导致小鼠和兔多发性肿瘤模型中的肿瘤生长显着延迟，副作用有限。我们在这里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。