IFN-γ-dependent NK cell activation is essential to metastasis suppression by engineered Salmonella

Abstract

Metastasis accounts for 90% of cancer-related deaths and, currently, there are no effective clinical therapies to block the metastatic cascade. A need to develop novel therapies specifically targeting fundamental metastasis processes remains urgent. Here, we demonstrate that Salmonella YB1, an engineered oxygen-sensitive strain, potently inhibits metastasis of a broad range of cancers. This process requires both IFN-γ and NK cells, as the absence of IFN-γ greatly reduces, whilst depletion of NK cells in vivo completely abolishes, the anti-metastatic ability of Salmonella. Mechanistically, we find that IFN-γ is mainly produced by NK cells during early Salmonella infection, and in turn, IFN-γ promotes the accumulation, activation, and cytotoxicity of NK cells, which kill the metastatic cancer cells thus achieving an anti-metastatic effect. Our findings highlight the significance of a self-regulatory feedback loop of NK cells in inhibiting metastasis, pointing a possible approach to develop anti-metastatic therapies by harnessing the power of NK cells.

Tumor Temporal Proteome Profiling Reveals the Immunological Triple Offensive Induced by Synthetic Anti-Cancer Salmonella

“…( Figure 1B , Supplementary Table 1 ). Overall, our results are in line with previous observation in Salmonella based tumor therapy, where Salmonella demonstrates an intrinsic anti-tumor effect, largely attributed to its immune stimulatory activity, as well as activation of both innate and adaptive immune cells ( 18 , 26 ).…”

“…NGP plays a role as a negative regulator of tumor vascular development and metastasis ( 31 ) ( Figure 1B ). Proteins in Module 5 were also enriched in positive regulation of T cell proliferation ( 32 ). Proteins in Module 6 were involved in B cell receptor signaling pathway and immunoglobulin mediated immune response.…”

“…The development of a “perfect” bacteria strain for cancer therapy relies greatly on the understanding of host–bacteria interactions ( 32 ). Our tumor proteome profiling systematically revealed the dynamics of the tumor proteome after YB1 treatment, which can be beneficial for uncovering the underlying immunological mechanism of YB1-mediated tumor shrink.…”

“…Proteins in Module 5 were also enriched in positive regulation of T cell proliferation (32). Proteins in Module 6 were involved in B cell receptor signaling pathway and immunoglobulin mediated immune response.…”

“…Systemic administration of Salmonella YB1 can effectively stimulate the immune system, resulting in the increased production of tumor necrosis factor-a (TNF-a), and interferon-g (IFN-g), as well as activation of both innate and adaptive immune cells (14)(15)(16)(17). These stimulated immune responses might create a hostile environment for tumor progression (18). However, the underlying systemic therapeutic mechanism of Salmonella YB1 remains to be elucidated.…”