Wang Heng, Xu Fang, Yao Chenlu, Dai Huaxing, Xu Jialu, Wu Bingbing, Tian Bo, Shi Xiaolin, Wang Chao
Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano and Soft Materials, Soochow University, Suzhou, Jiangsu 215123, China.
Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.
Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2412070121. doi: 10.1073/pnas.2412070121. Epub 2024 Dec 18.
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 (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.
近年来，抑制吲哚胺2,3-双加氧酶（IDO）用于抗癌治疗受到了广泛关注。然而，目前的IDO抑制剂面临着重大挑战，限制了它们的临床应用。在此，我们通过基因工程构建了一种高表达色氨酸的（L-Trp CB）菌株，该菌株在全身给药后能够严格定殖于肿瘤组织。我们发现，L-Trp CB产生的丁酸盐可抑制IDO活性，防止肿瘤中的色氨酸分解代谢和犬尿氨酸积累。此外，L-Trp CB释放的大量色氨酸可提供离散信号，支持肿瘤微环境中CD8+ T细胞的激活和能量代谢。我们观察到，L-Trp CB显著恢复了CD8+ T细胞的比例和功能，在小鼠和兔子的多种肿瘤模型中显著延缓了肿瘤生长，且副作用有限。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CD8+ T细胞反应来增强肿瘤免疫治疗。
