Tran Thanh Quang, Duysak Taner, Kim Kwangsoo, Dang Giang Chau, Yi Min-Hee, Choi Yoonjoo, Cho Jae Ho, Jeong Jae-Ho, Choy Hyon E
Departments of Microbiology & Immunology, Basic Medical Research Building, Chonnam National University Medical College, Hwasun, Jeonnam, South Korea.
Odysseus Bio, Basic Medical Research Building, Chonnam National University Medical College, Hwasun, Jeonnam, South Korea.
Oncogene. 2025 Jul 24. doi: 10.1038/s41388-025-03504-y.
Interleukin-2 (IL2) treatment has been explored as a potent immunotherapy agent, particularly for cancers, due to its ability to stimulate T cell proliferation and activity. However, significant challenges and limitations are associated with IL2 treatment, including its short half-life, systemic toxicity and side effects, and limited efficacy in solid tumors. In this study, we deployed an attenuated Salmonella Gallinarum (SG), an avian-specific pathogen capable of targeting tumor tissue, to express and secrete the IL2 using a bacterial flagellum type 3 secretion system (T3SS). Since the T3SS is used for the secretion of flagellin monomers (FliC), DNA of the human IL2 gene was fused to the SG fliC gene so that the fusion proteins would be exported together. A superb anti-cancer effect was observed when the SG expressing and secreting the FliC-IL2 fusion protein was injected into a syngeneic tumor mouse model with CT26 colorectal cancer via the tail vein. Within the fusion protein, the FliC moiety led to a selective increase in MHCIICD206 M1-like macrophages, while the IL2 moiety promoted selective expansion of cytotoxic CD8 T cells and NK cells, without expanding CD4FoxP3 regulatory T cells in the tumor microenvironment (TME). It was concluded that the local delivery of IL2 within the TME by cancer-targeting SG could overcome the limitations associated with IL2-based cancer immunotherapy.
白细胞介素-2（IL2）治疗已被探索作为一种有效的免疫治疗剂，特别是对于癌症，因为它能够刺激T细胞增殖和活性。然而，IL2治疗存在重大挑战和局限性，包括其半衰期短、全身毒性和副作用，以及在实体瘤中的疗效有限。在本研究中，我们利用减毒鸡沙门氏菌（SG），一种能够靶向肿瘤组织的禽类特异性病原体，通过细菌鞭毛3型分泌系统（T3SS）来表达和分泌IL2。由于T3SS用于分泌鞭毛蛋白单体（FliC），因此将人IL2基因的DNA与SG fliC基因融合，以便融合蛋白能够一起输出。当通过尾静脉将表达和分泌FliC-IL2融合蛋白的SG注射到患有CT26结直肠癌的同基因肿瘤小鼠模型中时，观察到了极好的抗癌效果。在融合蛋白中，FliC部分导致MHCII CD206 M1样巨噬细胞选择性增加，而IL2部分促进细胞毒性CD8 T细胞和NK细胞的选择性扩增，而不会在肿瘤微环境（TME）中扩增CD4 FoxP3调节性T细胞。得出的结论是，通过靶向癌症的SG在TME内局部递送IL2可以克服基于IL2的癌症免疫治疗的局限性。
