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. 2025 May 12;43(5):955-969.e10.
doi: 10.1016/j.ccell.2025.02.017. Epub 2025 Mar 6.

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

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

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

Sara Lamorte et al. Cancer Cell. .

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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Conflict of interest statement

Declaration of interests S.L. and T.L.M. have filed a provisional patent related to the work reported in the manuscript “Targeting IL-33 for cancer therapy. US Patent No. US63/600,618”.

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