Salmonella LVR01 induces dual innate immune memory responses in tumor models

Abstract

Innate immune memory operates in two modes: trained immunity, which amplifies cellular responsiveness, and tolerance, which reduces the immune response to later challenges. Agents such as beta-glucan, Leishmania, BCG, and LPS are known to trigger one of these effects. BCG, an established immunotherapy for bladder cancer, uses trained immunity to enhance anti-tumor adaptive responses. Salmonella has also shown potential in cancer treatment, generating strong but short-lived anti-tumor immune responses. This study investigates whether Salmonella LVR01 can induce trained immunity and how this influences anti-tumor activity. In vivo stimulation of bone marrow cells with Salmonella LVR01 was performed, followed by a secondary stimulus to evaluate trained immunity through cytokine production. The impact of Salmonella LVR01 on tumor growth and survival was examined in mouse models, with tumors implanted after bacterial administration. In vitro assays were conducted to measure cytokine production in mouse monocytes following stimulation with Salmonella. Salmonella LVR01 led to an increased cytokine response in bone marrow cells, consistent with trained immunity. This enhanced response was associated with slower tumor growth and improved survival in treated mice. However, in vitro studies showed that stimulation of monocytes with Salmonella resulted in reduced cytokine production, indicating immune tolerance. These dual effects may explain the temporary benefits of Salmonella-based cancer therapies, underscoring the need for further research to refine these treatments.