A TLR4-dependent fibroblast-monocyte axis in tumor-draining lymph nodes contributes to metastasis in triple-negative breast cancer
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-L1 hi ) 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.
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BibTeX
@article{mattavelli2026tlr4dependent,
title = {{A TLR4-dependent fibroblast-monocyte axis in tumor-draining lymph nodes contributes to metastasis in triple-negative breast cancer}},
author = {Greta Mattavelli and Moutaz Helal and Ana Cetkovic and Maximilian Krämer and Saskia-Laureen Herbert and Kilian Mielert and Tanja Schlaiß and Anna Frank and Emily Riemer and Mara John and Josefina del Pilar Martinez Vasquez and Laura Kindl and Jonathan Swietlik and Benedikt Gansen and Marion Krafft and Emilia Stanojkovska and Hanna Fischer and Ute-Susann Albert and Jonas Bauer and Murilo Delgobo and Arpa Aintablian and Haisam Alattar and Manfred Lutz and Felix Meissner and Thordur Oskarsson and Leo Rasche and Gustavo Ramos and Andreas Rosenwald and Achim Wöckel and Angela Riedel},
journal = {Immunity},
year = {2026},
month = oct,
doi = {10.1016/j.immuni.2025.08.015},
url = {https://hal.science/hal-05780876v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - A TLR4-dependent fibroblast-monocyte axis in tumor-draining lymph nodes contributes to metastasis in triple-negative breast cancer
AU - Greta Mattavelli
AU - Moutaz Helal
AU - Ana Cetkovic
AU - Maximilian Krämer
AU - Saskia-Laureen Herbert
AU - Kilian Mielert
AU - Tanja Schlaiß
AU - Anna Frank
AU - Emily Riemer
AU - Mara John
AU - Josefina del Pilar Martinez Vasquez
AU - Laura Kindl
AU - Jonathan Swietlik
AU - Benedikt Gansen
AU - Marion Krafft
AU - Emilia Stanojkovska
AU - Hanna Fischer
AU - Ute-Susann Albert
AU - Jonas Bauer
AU - Murilo Delgobo
AU - Arpa Aintablian
AU - Haisam Alattar
AU - Manfred Lutz
AU - Felix Meissner
AU - Thordur Oskarsson
AU - Leo Rasche
AU - Gustavo Ramos
AU - Andreas Rosenwald
AU - Achim Wöckel
AU - Angela Riedel
PY - 2026
DA - 2026/10/06
JO - Immunity
DO - 10.1016/j.immuni.2025.08.015
UR - https://hal.science/hal-05780876v1
AB - 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 hi ) 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.
SN - 1074-7613
ER -