Engineered Lactococcus lactis secreting Flt3L and OX40 ligand for in situ vaccination-based cancer immunotherapy

Junmeng Zhu, Yaohua Ke, Qin Liu, Ju Yang, Fangcen Liu, Ruihan Xu, Hang Zhou, Aoxing Chen, Jie Xiao, Fanyan Meng, Lixia Yu, Rutian Li, Jia Wei and Baorui Liu ()
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Junmeng Zhu: The Affiliated Hospital of Nanjing University Medical School
Yaohua Ke: The Affiliated Hospital of Nanjing University Medical School
Qin Liu: The Affiliated Hospital of Nanjing University Medical School
Ju Yang: The Affiliated Hospital of Nanjing University Medical School
Fangcen Liu: The Affiliated Hospital of Nanjing University Medical School
Ruihan Xu: The Affiliated Hospital of Nanjing University Medical School
Hang Zhou: The Affiliated Hospital of Nanjing University Medical School
Aoxing Chen: The Affiliated Hospital of Nanjing University Medical School
Jie Xiao: The Affiliated Hospital of Nanjing University Medical School
Fanyan Meng: The Affiliated Hospital of Nanjing University Medical School
Lixia Yu: The Affiliated Hospital of Nanjing University Medical School
Rutian Li: The Affiliated Hospital of Nanjing University Medical School
Jia Wei: The Affiliated Hospital of Nanjing University Medical School
Baorui Liu: The Affiliated Hospital of Nanjing University Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract In situ vaccination is a promising strategy to convert the immunosuppressive tumor microenvironment into an immunostimulatory one with limited systemic exposure and side effect. However, sustained clinical benefits require long-term and multidimensional immune activation including innate and adaptive immunity. Here, we develop a probiotic food-grade Lactococcus lactis-based in situ vaccination (FOLactis) expressing a fusion protein of Fms-like tyrosine kinase 3 ligand and co-stimulator OX40 ligand. Intratumoural delivery of FOLactis contributes to local retention and sustained release of therapeutics to thoroughly modulate key components of the antitumour immune response, such as activation of natural killer cells, cytotoxic T lymphocytes, and conventional-type-1-dendritic cells in the tumors and tumor-draining lymph nodes. In addition, intratumoural administration of FOLactis induces a more robust tumor antigen-specific immune response and superior systemic antitumour efficacy in multiple poorly immune cell-infiltrated and anti-PD1-resistant tumors. Specific depletion of different immune cells reveals that CD8+ T and natural killer cells are crucial to the in situ vaccine-elicited tumor regression. Our results confirm that FOLactis displays an enhanced antitumour immunity and successfully converts the ‘cold’ tumors to ‘hot’ tumors.

Date: 2022
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DOI: 10.1038/s41467-022-35130-7

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