تجاوز إلى المحتوى الرئيسي

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

ملخص البحث

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 FRCmonocyte 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.

مؤلف البحث
Greta Mattavelli, Moutaz Helal, Ana Cetkovic, Maximilian J. Krämer, Saskia-Laureen Herbert, Kilian Mielert, Tanja Schlaiss, Anna Frank, Emily Riemer, Mara John, Josefina del Pilar Martinez Vasquez, Laura Kindl, Jonathan J. Swietlik, Benedikt O. Gansen, Ma
تاريخ البحث
مجلة البحث
Immunity
مؤلف البحث
صفحات البحث
2830–2846.e15
الناشر
Elsevier (Cell Press)
تصنيف البحث
Q1
عدد البحث
58
موقع البحث
https://linkinghub.elsevier.com/retrieve/pii/S1074761325003784
سنة البحث
2025