A TLR4-dependent fibroblast-monocyte axis in tumor-draining lymph nodes contributes to metastasis in triple-negative breast cancer
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-L1<sup>hi</sup>) 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<sup>+</sup> 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.
Authors
- Murilo Delgobo (ORCID: https://orcid.org/0000-0003-4010-1909)
- Greta Mattavelli (ORCID: https://orcid.org/0009-0005-2208-7017)
- Jonathan J. Swietlik
- Manfred B. Lutz (ORCID: https://orcid.org/0000-0001-9193-1772)
- Thórdur Óskarsson (ORCID: https://orcid.org/0000-0002-0983-6969)
- Haisam Alattar (ORCID: https://orcid.org/0000-0003-2897-0407)
- Anna Katharina Frank (ORCID: https://orcid.org/0000-0003-1378-5129)
- Saskia-Laureen Herbert (ORCID: https://orcid.org/0000-0002-5810-9055)
- Leo Rasche (ORCID: https://orcid.org/0000-0002-9536-9649)
- Andreas Rosenwald (ORCID: https://orcid.org/0000-0001-7282-8374)
- Angela Riedel (ORCID: https://orcid.org/0009-0006-9411-4210)
- Mara John (ORCID: https://orcid.org/0000-0001-7147-405X)
- Jonas Bauer (ORCID: https://orcid.org/0000-0002-3328-7795)
- Achim Wöckel (ORCID: https://orcid.org/0000-0002-6767-9666)
- Tanja Schlaiß
- Emilia Stanojkovska
- H Fischer (ORCID: https://orcid.org/0000-0003-1959-7997)
- Moutaz Helal (ORCID: https://orcid.org/0000-0002-9561-1669)
- Emily Riemer
- Marion Krafft (ORCID: https://orcid.org/0000-0002-1076-2477)
- Kilian Mielert
- Felix Meissner (ORCID: https://orcid.org/0000-0003-1000-7989)
- Arpa Aintablian
- Melissa Kramer (ORCID: https://orcid.org/0000-0001-9669-3611)
- Benedikt Gansen
- Gustavo Ramos
- Ute‐Susann Albert
- Josefina Del Pilar
- Laura Kindl
- Ana Cetkovic
Institutions
- University of Bonn (DE)
- University of Würzburg (DE)
- Moffitt Cancer Center (US)
- Universitätsklinikum Würzburg (DE)
- Max Planck Institute of Biochemistry (DE)
- Assiut University (EG)
Publication Details
- Journal
- Immunity
- Published
- 2025-09-16
- DOI
- https://doi.org/10.1016/j.immuni.2025.08.015
- Citations
- 3
- Primary Topic
- Metastasis and carcinoma case studies
- Type
- article
- Field-Weighted Citation Impact
- 4.56