Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice

Stacy K. Thomas, Max M. Wattenberg, Shaanti Choi-Bose, Mark Uhlik, Ben Harrison, Heather Coho, Christopher R. Cassella, Meredith L. Stone, Dhruv Patel, Kelly Markowitz, Devora Delman, Michael Chisamore, Jeremy Drees, Nandita Bose and Gregory L. Beatty ()
Additional contact information
Stacy K. Thomas: University of Pennsylvania
Max M. Wattenberg: University of Pennsylvania
Shaanti Choi-Bose: University of Pennsylvania
Mark Uhlik: HiberCell Inc
Ben Harrison: HiberCell Inc
Heather Coho: University of Pennsylvania
Christopher R. Cassella: University of Pennsylvania
Meredith L. Stone: University of Pennsylvania
Dhruv Patel: University of Pennsylvania
Kelly Markowitz: University of Pennsylvania
Devora Delman: University of Pennsylvania
Michael Chisamore: Merck & Co., Inc.
Jeremy Drees: HiberCell Inc
Nandita Bose: HiberCell Inc
Gregory L. Beatty: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to β-glucan (odetiglucan) treatment by inhibiting liver metastasis. β-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of β-glucan, which also required T cells. Furthermore, β-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.

Date: 2023
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DOI: 10.1038/s41467-023-41771-z

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