Gastroenterology · 2026
Neutrophil-Driven Trogocytosis in Pancreatic Ductal Adenocarcinoma Liver Metastases Restrains Immunosuppressive Macrophage Polarization and Limits Metastatic Progression.
СтатьяНазвание и аннотация: Перевод в очереди
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Belz Larissa, van den Heuvel Dominic, Kilani Badr, Martinez-Navarro Alejandro, Akhalkatsi Anastassia, Joppich Markus, Zhu Yinfeng, Ding Qiongjie, Wan Jinlong, Stermann Julia, Winterhalter Julia, Messerer Denise, Titova Anna, Balaji Sanjana, Giri Santoshi, Eivers Luke, Widholz Sebastian, Bärthel Stefanie, Raatz Elisabeth, Saur Dieter, Lauber Kirsten, Beyer Georg, Mayerle Julia, Ormanns Steffen, Guenther Michael, Massberg Steffen, Ishikawa-Ankerhold Hellen, Stark Konstantin
Аннотация
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) metastasizes early and frequently to the liver, limiting therapeutic options and resulting in poor prognosis. Neutrophils are key immune players in cancer progression, yet their role in PDAC liver metastases remains unclear. This study investigates how neutrophils influence hepatic macrophages and modulate the immune landscape in the metastatic microenvironment using intravital calcium imaging and single-cell RNA sequencing.
METHODS: Intravital microscopy was used to monitor neutrophil behavior and interactions within the metastatic niche. We used intravital calcium imaging in LysMcre-PCG5-tdt mice to visualize real-time immune cell interactions and their functional impact in a PDAC metastasis model. To dissect the effect of neutrophils on the immune landscape, we performed single-cell RNA sequencing of liver-infiltrating leukocytes in tumor-bearing mice.
RESULTS: Intravital calcium imaging revealed that neutrophils are recruited to hepatic metastases by CCL2/CCL5, where they take up tumor cell fragments via trogocytosis and subsequently present these tumor fragments to hepatic macrophages. This neutrophil-driven immunomodulation was abolished on neutrophil depletion, resulting in a permissive tumor-promoting macrophage phenotype. Single-cell RNA sequencing identified distinct macrophage subpopulations, demonstrating that neutrophils suppress the development of immunosuppressive macrophages by C3-dependent signaling and enhance antitumor pathways.
CONCLUSIONS: This study provides in vivo evidence of neutrophil-macrophage crosstalk in PDAC liver metastases and highlights the functional consequences of neutrophil depletion. By integrating intravital calcium imaging with single-cell RNA sequencing, we uncovered a previously unrecognized mechanism of neutrophil-driven immunomodulation, emphasizing the potential for therapeutic strategies targeting neutrophil-macrophage interactions in metastatic PDAC.
METHODS: Intravital microscopy was used to monitor neutrophil behavior and interactions within the metastatic niche. We used intravital calcium imaging in LysMcre-PCG5-tdt mice to visualize real-time immune cell interactions and their functional impact in a PDAC metastasis model. To dissect the effect of neutrophils on the immune landscape, we performed single-cell RNA sequencing of liver-infiltrating leukocytes in tumor-bearing mice.
RESULTS: Intravital calcium imaging revealed that neutrophils are recruited to hepatic metastases by CCL2/CCL5, where they take up tumor cell fragments via trogocytosis and subsequently present these tumor fragments to hepatic macrophages. This neutrophil-driven immunomodulation was abolished on neutrophil depletion, resulting in a permissive tumor-promoting macrophage phenotype. Single-cell RNA sequencing identified distinct macrophage subpopulations, demonstrating that neutrophils suppress the development of immunosuppressive macrophages by C3-dependent signaling and enhance antitumor pathways.
CONCLUSIONS: This study provides in vivo evidence of neutrophil-macrophage crosstalk in PDAC liver metastases and highlights the functional consequences of neutrophil depletion. By integrating intravital calcium imaging with single-cell RNA sequencing, we uncovered a previously unrecognized mechanism of neutrophil-driven immunomodulation, emphasizing the potential for therapeutic strategies targeting neutrophil-macrophage interactions in metastatic PDAC.
Предметные рубрики MeSH
AnimalsCarcinoma, Pancreatic DuctalPancreatic NeoplasmsLiver NeoplasmsNeutrophilsTumor MicroenvironmentMacrophagesDisease ProgressionMiceHumansChemokine CCL2Chemokine CCL5Cell Line, TumorIntravital MicroscopyTumor-Associated MacrophagesFemaleCell CommunicationMice, Inbred C57BLNeutrophil InfiltrationSingle-Cell Analysis