Salmonella blocks cancer cell metastasis through IFN-[gamma]-dependent NK cell activation

Abstract

Metastasis, which leads to the development of secondary tumors all over the body, causes 90% of cancer-related deaths. During the long journey of metastasis, metastatic cancer cells dynamically interact with their surrounding microenvironments and most of these metastatic cancer cells are likely to die, especially during the colonization process at distant target organs. At last, only around ≤0.01% of the cancer cells that leave the primary tumor lesion can successfully develop into metastatic tumors at distant organs. This bottleneck of cancer metastasis results in the secondary metastatic tumors being significantly different from the primary tumors in many aspects, causing the originally effective cancer therapies on primary tumors to show limited or even no therapeutic effect on secondary metastatic tumors. However, current clinical and preclinical cancer therapies are usually validated based on their ability to suppress the growth of primary tumors, ignoring the effect on metastasis. As a result, no effective anti-metastatic therapies exist clinically, and novel preventive and therapeutic strategies and agents specifically targeting metastasis are urgently needed. Based on previous findings that Salmonella YB1, an engineered oxygen-sensitive strain, inhibited metastasis of breast cancer and colon cancer, systematic studies have been performed on metastasis suppression induced by Salmonella YB1. My systemic mechanism research showed that Salmonella YB1 potently inhibits the metastasis of a broad range of cancers, regardless of the cancer types and the host genetic backgrounds. This process required both IFN-γ and NK cells, as the absence of IFN-γ greatly reduced, whilst depletion of NK cells in vivo completely abolished, the anti-metastatic ability of Salmonella YB1. Mechanistically, it was found that IFN-γ was mainly produced by NK cells during early Salmonella YB1 infection, and in turn, IFN-γ promoted the accumulation, activation, and cytotoxicity of NK cells at a later stage. Finally, these activated NK cells suppressed the early survival of metastatic cancer cells in the target organ (e.g., the lung) of metastasis and thus achieving an anti-metastatic effect. These findings demonstrated in this thesis highlight the significance of a self-regulatory feedback loop of NK cell activation in inhibiting metastasis, pointing to a possible approach to develop anti-metastatic therapies by harnessing the power of activated NK cells.