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

  • Nat Commun. 2023 Oct 10;14(1):6330. doi: 10.1038/s41467-023-41771-z.
Stacy K Thomas  1  2 ,  Max M Wattenberg  1  2 ,  Shaanti Choi-Bose  1  2 ,  Mark Uhlik  3  4 ,  Ben Harrison  3 ,  Heather Coho  1  2 ,  Christopher R Cassella  1  2 ,  Meredith L Stone  1  2 ,  Dhruv Patel  1  2 ,  Kelly Markowitz  1  2 ,  Devora Delman  1  2 ,  Michael Chisamore  5 ,  Jeremy Drees  3 ,  Nandita Bose  3 ,  Gregory L Beatty  6  7
Affiliations
  • 1. Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 3. HiberCell Inc, Roseville, MN, USA.
  • 4. OncXerna, Waltham, MA, USA.
  • 5. Merck & Co., Inc., Kenilworth, NJ, USA.
  • 6. Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 7. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
PMID: 37816712 DOI: 10.1038/s41467-023-41771-z
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.

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