Abstract 2483: Attenuated Salmonella blocks cancer metastasis by activating NK cells in an IFN-γ-dependent manner

Abstract Introduction and Objectives: The recent remarkable clinical results of cancer immunotherapies, such as immune checkpoint blockade and chimeric antigen receptor T cells (CAR-T), has sparked a great deal of enthusiasm in manipulating the immune response in the fight against cancer. Bacterial cancer therapies represent an alternative approach to targeting solid tumors for evoking anti-tumor immune responses. As a facultative anaerobic pathogen that can penetrate and colonize solid tumors, Salmonella typhimurium gained lot of interest in the investigation of bacterial cancer therapies and can exert its intrinsic antitumor activity by directly inducing systemic immune responses. However, most bacterial cancer therapies, including salmonella-based cancer therapies, have mainly focused on the suppression of already established tumors rather than metastasis. 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 tumor 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. Experimental Procedures and Outcomes: 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. Further study showed that suppression of cancer metastasis by attenuated Salmonella only requires the innate immune response. Among the many induced cytokines, we identified IFN-γ as an indispensable factor for inhibiting cancer metastasis. Based on CyTOF (mass cytometry or cytometry by time of flight) analysis of the innate immune responses after Salmonella treatment and antibody-mediated cell depletion, we further demonstrated that NK cells are the major factor involved in Salmonella-provoked metastasis suppression. 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. Citation Format: Li Rong, Qiubin Lin, Shuhai Lin, Guo Fu, Jiandong Huang. Attenuated Salmonella blocks cancer metastasis by activating NK cells in an IFN-γ-dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2483.