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
  • 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: [email protected].
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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