Abstract P94: Cross-Talk of Hepatic Innate Immune Cells in Maintaining Liver Health and Shaping Metastatic Susceptibility

Abstract

Up to 50% of patients undergoing treatment for malignancies develop liver metastases during the course of their disease. In the United States and Europe, liver metastases are more prevalent than primary liver cancer. Tissue-resident immune cells are pivotal regulators of the local microenvironment, with macrophages playing fundamental roles in tumour initiation and progression. In the liver, Kupffer cells (KCs)—the dominant tissue-resident macrophages—constitute a substantial fraction of the immune landscape and are essential for maintaining liver homeostasis. To determine whether KCs contribute to shaping the pre-metastatic niche, we are investigating the communication dynamics between KCs and other hepatic immune cells, and how these interactions evolve in diseased tissues using various murine models. Our preliminary findings identify a distinct subset of KCs with unique transcriptional and functional profiles. Notably, these KCs engage in cross-talk with innate lymphoid cells (ILCs), particularly ILC1s. We have observed that granulocyte-macrophage colony-stimulating factor (GM-CSF) production by ILC1s primes KCs to maintain tissue fitness. In the absence of GM-CSF, KC function is compromised, leading to increased tumour burden in vivo. Given the complexity of the gut–liver axis, we also explored how host–microbiota interactions influence KC behaviour and priming. Our data suggest that microbial cues can modulate ILC1–KC communication, further shaping the immune landscape of the liver. These findings reveal a previously underappreciated axis of communication between KCs and ILC1s, providing deeper insight into the immune dynamics of the liver microenvironment. Our results underscore the role of tissue-resident macrophages not only in preserving tissue integrity but also in influencing disease progression. These findings lay the groundwork for therapeutic strategies that selectively modulate immune cross-talk to potentially prevent metastatic progression in the liver. (278 words)