1.Intranodal injection of neoantigen-bearing engineered Lactococcus lactis triggers epitope spreading and systemic tumor regressions.
Junmeng ZHU ; Yi SUN ; Xiaoping QIAN ; Lin LI ; Fangcen LIU ; Xiaonan WANG ; Yaohua KE ; Jie SHAO ; Lijing ZHU ; Lifeng WANG ; Qin LIU ; Baorui LIU
Acta Pharmaceutica Sinica B 2025;15(4):2217-2236
Probiotics are natural systems bridging synthetic biology, physical biotechnology, and immunology, initiating innate and adaptive anti-tumor immune activity. We previously constructed an all-in-one engineered food-grade probiotic Lactococcus lactis (FOLactis) which could boost the crosstalk among different immune cells such as dendritic cells (DCs), natural killer cells, and T cells. Herein, considering the limited clinical efficacy of naked personalized neoantigen peptide vaccines, we decorate FOLactis with tumor antigens by employing a Plug-and-Display system comprising membrane-inserted peptides. Intranodal injection of FOLactis coated with neoantigen peptides (Ag-FOLactis) induces robust DCs presentation and neoantigen-specific cellular immunity. Notably, Ag-FOLactis not only triggers a 45-fold rise in the quantity of locally reactive neoantigen-specific T cells but also induces epitope spreading in both subcutaneous and metastatic tumor-bearing models, leading to potent inhibition of tumor growth. These findings imply that Ag-FOLactis represents a powerful platform to rapidly and easily display antigens, facilitating the development of a bio-activated platform for personalized therapy.

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