2. Academic Validation
  3. A TLR4-dependent fibroblast-monocyte axis in tumor-draining lymph nodes contributes to metastasis in triple-negative breast cancer

A TLR4-dependent fibroblast-monocyte axis in tumor-draining lymph nodes contributes to metastasis in triple-negative breast cancer

  • Immunity. 2025 Sep 15:S1074-7613(25)00378-4. doi: 10.1016/j.immuni.2025.08.015.
Greta Mattavelli 1,  Moutaz Helal 1,  Ana Cetkovic 1,  Maximilian J Krämer 1,  Saskia-Laureen Herbert 2,  Kilian Mielert 3,  Tanja Schlaiß 2,  Anna Frank 1,  Emily Riemer 1,  Mara John 1,  Josefina Del Pilar Martinez Vasquez 1,  Laura Kindl 1,  Jonathan J Swietlik 4,  Benedikt O Gansen 5,  Marion Krafft 1,  Emilia Stanojkovska 1,  Hanna Fischer 1,  Ute-Susann Albert 2,  Jonas Bauer 2,  Murilo Delgobo 6,  Arpa Aintablian 7,  Haisam Alattar 8,  Manfred B Lutz 7,  Felix Meissner 9,  Thordur Oskarsson 10,  Leo Rasche 11,  Gustavo Ramos 6,  Andreas Rosenwald 3,  Achim Wöckel 2,  Angela Riedel 12
Affiliations

Affiliations

  • 1 Mildred Scheel Early Career Centre (MSNZ) for Cancer Research Würzburg, University Hospital Würzburg and University Würzburg, Würzburg, Germany.
  • 2 Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany.
  • 3 Institute of Pathology, University of Würzburg, Würzburg, Germany.
  • 4 Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 5 Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, Bonn, Germany.
  • 6 Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany.
  • 7 Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
  • 8 Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany; Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, Egypt.
  • 9 Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany; Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, Bonn, Germany.
  • 10 Department of Molecular Oncology and Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • 11 Mildred Scheel Early Career Centre (MSNZ) for Cancer Research Würzburg, University Hospital Würzburg and University Würzburg, Würzburg, Germany; Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
  • 12 Mildred Scheel Early Career Centre (MSNZ) for Cancer Research Würzburg, University Hospital Würzburg and University Würzburg, Würzburg, Germany; Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany. Electronic address: angela.riedel@uni-wuerzburg.de.
PMID: 40957419 DOI: 10.1016/j.immuni.2025.08.015
Abstract

Tumor-draining lymph nodes (TDLNs) are sites of anti-tumor immune priming as well as metastases. Here, we examined how the cellular networks within TDLNs are reorganized in triple-negative breast Cancer (TNBC). We found that the frequencies of programmed death ligand 1 high (PD-L1hi) monocytes increased in TDLNs of metastatic TNBC mouse tumors. Fibroblastic reticular cell (FRC) subtypes heightened the expression of the chemokines CCL2 and CCL7, supporting the homing of CCR2+ monocytes. These monocytes suppressed T cells in vitro via PD-L1 and inducible nitric oxide synthase (iNOS). Spatial transcriptomics revealed immunosuppressive FRC-monocyte niches in vascularized and T cell areas. Tumor-associated Toll-like Receptor (TLR) 4 ligands induced CCL2 and CCL7 expression by FRCs to promote monocyte recruitment. Localized TLR4 inhibition in combination with anti-programmed cell death protein 1 (αPD-1) therapy reduced monocyte homing and boosted T cell function, ultimately attenuating lung metastases. Monocytes accumulate in human TNBC TDLNs, with evidence of a FRC-monocyte axis, and a TLR4 ligand signature is predictive of poor survival outcomes in TNBC patients. Thus, metastatic TNBC can reprogram lymph nodes (LNs) to facilitate PD-L1-mediated immune evasion and metastasis.

Keywords

fibroblastic reticular cells; immunosuppressive monocytes; immunotherapy; metastasis; pre-metastatic niche; single-cell sequencing; spatial transcriptomics; triple-negative breast cancer; tumor microenvironment; tumor-draining lymph node.

Figures
Products