IFN-γ-dependent NK cell activation is essential to metastasis suppression by engineered Salmonella
Qiubin Lin, Rong Li, Xian Jia, Renhao Li, Bin Yu, Jingchu Hu, Xiao Luo, Smaranda Badea, Xu Chen, Guofeng Fu, Kejiong Lai, Ming-chun Lee, Bao‐Zhong Zhang, Hua‐Rui Gong, Nan Zhou, Xiao Lei Chen, Shuhai Lin, Guo Fu, Jian‐Dong Huang, Guo Fu, Jian‐Dong Huang
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.