Therapeutic bacteria-trained NK cells confer long-term protection against cancer metastasis

Area of Science:

• Immunology
• Cancer Biology
• Microbiology

Background:

• Metastasis is responsible for 90% of cancer deaths, with limited preventive strategies.
• Therapeutic bacteria, like Salmonella, show anti-tumor potential.
• Natural Killer (NK) cells are crucial immune components.

Purpose of the Study:

• To investigate if therapeutic Salmonella can prevent cancer metastasis.
• To understand the mechanisms by which Salmonella induces long-lasting anti-metastatic protection.
• To compare the efficacy of Salmonella-induced trained NK cells against conventional therapies.

Main Methods:

• Administered a single dose of therapeutic Salmonella to mice.
• Performed integrated functional and multi-omics analyses on Natural Killer (NK) cells.
• Assessed NK cell epigenome, signaling pathways, and effector functions (IFN-γ release, cytotoxicity).
• Investigated the roles of IL-12 and IL-18 in NK cell training.
• Compared the anti-metastatic efficacy of trained NK cells with PD-1 and TIGIT blockade.

Main Results:

• Salmonella induced long-lasting protection against metastasis by generating "trained" NK (stNK) cells.
• stNK cells exhibited an enduring reprogrammed epigenome with enhanced pro-survival signaling and effector functions.
• stNK cells showed more potent IFN-γ release and cytotoxicity upon secondary stimulation.
• NK cell training required a transient pulse of IL-12 and sustained IL-18 signaling.
• stNK cells demonstrated superior anti-metastatic activity compared to PD-1 and TIGIT blockade.

Conclusions:

• Therapeutic Salmonella can induce trained NK cells for effective and long-lasting metastasis prevention.
• Trained NK cells offer a novel immunological strategy superior to current immune checkpoint inhibitors.
• Bacterial cancer vaccines or trained NK cells hold significant potential for combating metastasis.