Abstract 1391: Therapeutic salmonella induces long-term protective trained immunity in NK cells against metastasis

Abstract

Abstract Immune memory is a trait commonly associated with adaptive immunity. Nevertheless, it has been observed that activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers, a form of innate immune memory known as trained immunity. This phenomenon has been primarily explored in the context of host defense against infectious disease, where myeloid cells, including monocytes, macrophages, and their precursor cells, are conditioned by specific stimuli such as β-glucan, LPS, or the bacillus Calmette-Guιrin (BCG) to boost protection against microbial pathogens. However, the induction of trained immunity in innate lymphocytes, particularly through these known or yet-to-be-discovered stimuli and its explicit contribution to tumor immunity, remain insufficiently characterized. Metastasis accounts for 90% of cancer-related deaths, and no effective clinical therapies are currently available to halt the metastatic cascade. Based on multiple cancer metastasis mouse models and immunological analysis, we found that a single dose of therapeutic Salmonella YB1, an engineered oxygen-sensitive strain, provides extensive and persistent protection against metastasis by inducing protective trained immunity in NK cells, consistently observed irrespective of the mouse genetic background or cancer cell lines. Following inflammatory resolution, salmonella YB1-trained NK cells exhibit an enhanced capacity to release IFN-γ upon secondary stimulation and increased cytotoxicity towards cancer cells, which is associated with epigenetic changes. Further investigation using single-cell transcriptomic profiling indicates that the formation of long-term anti-metastatic trained immunity in NK cells by Salmonella YB1 is dependent on IL12 and IL18. Additionally, Salmonella YB1-trained NK cells outperform common immune checkpoint therapies like PD1 blockade and TIGIT blockade in suppressing metastasis. In summary, our results revealed a novel anti-metastatic function of trained NK cells induced by therapeutic Salmonella, suggesting the induction of trained immunity in NK cells as a potential anti-tumor strategy. Citation Format: Li Rong, Jiandong Huang. Therapeutic salmonella induces long-term protective trained immunity in NK cells against metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1391.