Abstract 1178: In vivo, visualization of immune cell dynamics upon the arrival of liver metastatic cells reveals the initiation of initial intravascular immune responses against pioneering tumor cells

Abstract Tumor metastases are the main cause of cancer-related death. The liver is one of the most frequently targeted organs in cancer and liver metastases are known to promote systemic immunosuppression and poor response to immunotherapy. The liver is an immune-privileged organ that is characterized by tissue-specific immune reactions defined by its particular architecture, exposure to toxic compounds and resident immune cell populations. The nature of the liver organ-specific immune response that is orchestrated upon tumor cell arrival has been poorly described and can define the nature immune response elicited against metastasis. We hypothesize that the first steps of cancer cell metastasis shape immune responses to liver metastases conditioning the evolution of cancer cells in the metastatic niche. By performing intravital microscopy in the liver of several immune-cell reporter mice bearing subcutaneous tumors and intrasplenic injection of syngeneic colorectal cancer and melanoma cell lines we characterized the dynamics of immune responses against tumor cells from NK, T cell, dendritic cells and macrophages at very early time points upon tumor cell arrival. We observed active surveillance of the premetastatic niche by T cells, a subset of circulating dendritic cells and NK cells with different dynamics and behavior within the liver niche. Specifically, T cells and, mainly CD4+ T cells, patrol the liver sinusoids in the absence of metastatic cells and frequently perform short interactions with resident Kupffer cells in a process that is modulated by GPCRs but not by resident liver macrophages. We also observed that DCs also crawl over the sinusoids over long periods of time. Tumor cells arriving at the liver rapidly break in vesicles that were usually uptaken by circulating or liver resident leukocytes. In particular, efferocytosis of large pieces of tumor cells and tumor cell fragments by resident Kupfer cells was frequently observed in our time-lapse microscopy videos. Intravascular clusters of T cells and DCs but not of NK cells were effectively formed in areas where tumor cell antigenic material was observed within phagocytes in a chemokine receptor-dependent fashion. However large tumor cell clusters created local hypoxic conditions that limited T cell motility and dendritic cell infiltration. Our works report for the first time that the liver is under constant immune surveillance by different immune cell subsets due to its particular vasculature, flow conditions and environment. We have been also able to describe the elicitation of mixed and local immune responses to metastasizing tumor cells shortly upon tumor cell arrival and nidification within the liver niche. Citation Format: Beatrice Pinci, Almudena Manzanal, Carlos Luri-Rey, Maria Lucia Chiclana, David Causapé, Ignacio Melero, Alvaro Teijeira. In vivo, visualization of immune cell dynamics upon the arrival of liver metastatic cells reveals the initiation of initial intravascular immune responses against pioneering tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1178.