2. Academic Validation
  3. Lymph node macrophages drive immune tolerance and resistance to cancer therapy by induction of the immune-regulatory cytokine IL-33

Lymph node macrophages drive immune tolerance and resistance to cancer therapy by induction of the immune-regulatory cytokine IL-33

  • Cancer Cell. 2025 Mar 5:S1535-6108(25)00069-8. doi: 10.1016/j.ccell.2025.02.017.
Sara Lamorte 1,  Rene Quevedo 1,  Robbie Jin 1,  Luke Neufeld 1,  Zhe Qi Liu 1,  M Teresa Ciudad 1,  Sabelo Lukhele 1,  Jessica Bruce 2,  Shreya Mishra 3,  Xin Zhang 1,  Zaid Kamil Saeed 4,  Hal Berman 5,  Dana J Philpott 6,  Stephen E Girardin 2,  Shane Harding 7,  David H Munn 8,  Tak W Mak 3,  Mikael C I Karlsson 9,  David G Brooks 1,  Tracy L McGaha 10
Affiliations

Affiliations

  • 1 Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 2 Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, ON, Canada.
  • 3 Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
  • 4 Department of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, ON, Canada.
  • 5 Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, The University of Toronto, Toronto, ON, Canada.
  • 6 Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 7 Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medical Biophysics, The University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 8 Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
  • 9 Department of Microbiology, Tumor, and Cell Biology, The Karolinska Institute, 171 77 Stockholm, Sweden.
  • 10 Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Immunology, The University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: tracy.mcgaha@uhn.ca.
PMID: 40054466 DOI: 10.1016/j.ccell.2025.02.017
Abstract

Apoptotic cells are immunosuppressive, creating a barrier in Cancer treatment. Thus, we investigated immune responses to dying tumor cells after therapy in the tumor draining lymph node (TDLN). A key population responsible for clearing tumor material in the TDLN was medullary sinus macrophages (MSMs). Tumor debris phagocytosis by MSMs induces the cytokine IL-33, and blocking the IL-33 receptor (ST2) or deletion of Il33 in MSMs enhances therapy responses. Mechanistically, IL-33 activates T regulatory cells in TDLNs that migrate to the tumor to suppress CD8+ T cells. Therapeutically combining ST2 blockade, targeted kinase inhibitors, and anti-PD-1 immunotherapy increases CD8+ T cell activity promoting tumor regression. Importantly, we observe similar activity in human macrophages, and IL-33 expression in sentinel lymph nodes correlates with disease stage and survival in melanoma. Thus, our data identifies an IL-33-dependent immune response to therapy that attenuates therapy-induced anti-tumor immunity.

Keywords

Treg cell; cancer therapy; cell death; cytokines; immune suppression; lymph node; macrophage.

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