7P - Engineered salmonella blocks cancer metastasis by activating NK cells in an IFN-γ-dependent manner

Background

Metastasis accounts for 90% of cancer related deaths and blocking of metastatic cascade has critical clinical impact. However, the clinical drug development for cancer treatment, including cancer immunotherapies, is evaluated largely depending on their ability to cause tumour shrinkage and ignores the effect on metastasis as it has proven challenging to target. Therefore, there is an urgent need for novel therapeutic strategies and agents targeting metastasis. Using an attenuated Salmonella typhimurium strain YB1 engineered by our lab, we have found a potent suppressive effect of attenuated Salmonella on cancer metastasis, regardless of cancer types and genetic background, by evoking strong anti-metastatic immune response.

Methods

Mutant mice and antibody-mediated cell depletion were used to identify the host genetic and cellular requirement for the bacterial supression of cancer cell metastasis. CyTOF (mass cytometry or cytometry by time of flight) was used to investigate the the innate immune responses after Salmonella treatment.

Results

Our studies showed that suppression of cancer metastasis by attenuated Salmonella only requires the innate immune response. Among the many induced cytokines, IFN-γ was identified as an indispensable factor for inhibiting cancer metastasis. CyTOF and antibody-mediated cell depletion analysis of the innate immune responses after Salmonella treatment, revealed that NK cells are the major factor involved in Salmonella-provoked metastasis suppression.

Conclusions

We found that IFN-γ was mainly produced by NK cells during early Salmonella infection, and in turn, IFN-γ promoted the accumulation, activation and cytotoxicity of NK cells. The IFN-γ-dependent NK cells directly eliminated newly accumulated cancer cells in the lung to block the cancer metastasis cascade in response to the Salmonella treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

This work was supported by grants from the Shenzhen Peacock Team Project (KQTD2015033117210153) and Shenzhen Science and Technology Innovation Committee Basic Science Research Grant (JCYJ20170413154523577).

Disclosure

All authors have declared no conflicts of interest.