Trained innate immunity with BCG enhances inflammasome activation and protection in infectious diseases and cancer 2820

Abstract Description The BCG can elicit enhanced innate immune responses against a wide range of infections and cancer known as trained immunity. Here, we used a bacterial infection model Brucella abortus that is the causative agent of brucellosis. In this study, we demonstrate that C57BL/6 mouse macrophages under BCG training enhance inflammatory responses against B. abortus. BCG-trained macrophages showed increased MHC-II and CD40 expression on the cell surface and higher IL-6, IL-12 and IL-1β production. The increase in IL-1β secretion was accompanied by enhanced activation of canonical and non-canonical inflammasome platforms. From a metabolic point of view, signaling through the Akt/mTOR/S6K pathway was also enhanced. In vivo, we monitored a significant reduction in the bacterial burden in organs from BCG-trained C57BL/6 mice when compared to the untrained group. Regarding the tumor model, we used MB49 syngeneic mouse bladder cancer. Thirty days prior to local BCG treatment in the tumor, mice were pre-immunized with BCG to induce trained immunity. BCG pre-immunized animals enhanced the numbers of neutrophils, macrophages and CD8+ T cells in tumor microenvironment (TME). This augmented immune cell migration in TME was associated with elevated levels of IL-6, TNF-α and IFN-γ. We also observed a metabolic reprogramming with activation of the Akt/mTOR/S6K/HIF1α pathway that culminate in reduced tumor volume in BCG-vaccinated animals compared to control mice. Funding Sources Supported by FAPESP, grants #2022/15358-7 and 2023/02577-5) and National Institutes of Health (Grant R01 AI116453). Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)