Wu Yumin, Liu Bo, Yan Yifan, Gong Chuntao, Wang Kaiwei, Liu Nanhui, Zhu Yujie, Li Maoyi, Wang Chunjie, Yang Yizhe, Feng Liangzhu, Liu Zhuang
Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, China.
InnoBM Pharmaceuticals, Suzhou, 215123, Jiangsu, China.
Nat Commun. 2024 Dec 3;15(1):10503. doi: 10.1038/s41467-024-54883-x.
Incomplete tumor removal after microwave ablation (MWA), a widely used hyperthermia-based therapy, can result in tumor recurrence. Herein, attenuated Salmonella typhimurium VNP20009 is engineered to release interleukin-15&interleukin-15-receptor-alpha (IL-15&IL-15Rα) in response to mildly elevated temperature. Such 15&15R@VNP colonizes in tumors upon intravenous injection, and the expression of IL-15&IL-15Rα is triggered by MWA. Anti-tumor immune responses are elicited, efficiently suppressing tumor growth even after incomplete microwave ablation. We further design VNP20009 with thermal-responsive co-expression of both IL-15&IL-15Rα and soluble programmed cell death protein (sPD-1). Such sPD-1-15&15R@VNP can also reverse the functional suppression of immune cells driven by PD-1/PD-L1 axis, reinvigorating progenitor exhausted T cells, a critical subset of cytotoxic T lymphocytes responsive to immune checkpoint blockade. Such thermal-responsive engineered bacteria are thus a promising adjuvant therapy to potentiate tumor ablation therapies via effectively activating antitumor immunity.
微波消融（MWA）是一种广泛应用的基于热疗的治疗方法，肿瘤切除不完全会导致肿瘤复发。在此，经过基因工程改造的减毒鼠伤寒沙门氏菌VNP20009可在温度轻度升高时释放白细胞介素-15和白细胞介素-15受体α（IL-15&IL-15Rα）。静脉注射后，这种15&15R@VNP会在肿瘤中定植，微波消融会触发IL-15&IL-15Rα的表达。引发抗肿瘤免疫反应，即使在微波消融不完全后也能有效抑制肿瘤生长。我们进一步设计了VNP20009，使其热响应性共表达IL-15&IL-15Rα和可溶性程序性细胞死亡蛋白（sPD-1）。这种sPD-1-15&15R@VNP还可以逆转由PD-1/PD-L1轴驱动的免疫细胞功能抑制，使祖细胞耗竭的T细胞恢复活力，祖细胞耗竭的T细胞是对免疫检查点阻断有反应的细胞毒性T淋巴细胞的关键亚群。因此，这种热响应性工程菌是一种很有前景的辅助治疗方法，可通过有效激活抗肿瘤免疫来增强肿瘤消融治疗效果。
