Thermal-responsive activation of engineered bacteria to trigger antitumor immunity post microwave ablation therapy

Yumin Wu, Bo Liu, Yifan Yan, Chuntao Gong, Kaiwei Wang, Nanhui Liu, Yujie Zhu, Maoyi Li, Chunjie Wang, Yizhe Yang, Liangzhu Feng () and Zhuang Liu ()
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Yumin Wu: Soochow University
Bo Liu: Soochow University
Yifan Yan: Soochow University
Chuntao Gong: InnoBM Pharmaceuticals
Kaiwei Wang: Soochow University
Nanhui Liu: Soochow University
Yujie Zhu: Soochow University
Maoyi Li: Soochow University
Chunjie Wang: Soochow University
Yizhe Yang: Soochow University
Liangzhu Feng: Soochow University
Zhuang Liu: Soochow University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54883-x

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