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

ABSTRACT: Triple-negative breast cancer (TNBC) is the most aggressive form of BC and despite improvements in neoadjuvant treatment with immune checkpoint blockade (ICB) targeting PD-1, response rates vary, and patients relapse with metastatic disease. Using human samples and mouse models, we show that myeloid cells, particularly monocytes, increase in aggressive TNBC draining lymph nodes (TDLN) showing T-cell suppressive capacity via PD-L1 and iNOS. Tumor-induced TLR4 ligands reprogrammed TDLN fibroblastic reticular cells (FRCs) through TLR4 activation to induce the recruitment of monocytes via CCL2 and CCL7 in vascularized and T-cell areas. Indeed, monocytes expressing the receptor of CCL2/7 CCR2 home to and colocalize with FRC-rich niches. The local inhibition of this recruitment axis at the TDLN site, either through CCR2 or TLR4 inhibition, in combination with PD-1 blocking, resulted in reduced LN and distant lung metastasis in mouse models. A subset of TNBC patients with worse survival was stratified using TLR4 ligands, including TNC, S100A9, and FN1. Our results thus demonstrate a novel mechanism through which metastatic TNBC tumors reprogram the TDLN-niche to facilitate PD-L1-mediated immune evasion that precedes and drives metastasis. We thereby provide an opportunity to improve the efficacy of ICB in TNBC patients and to use the TDLN or our primary tumor signature as predictive biomarkers.

ORGANISM(S): Mus musculus

PROVIDER: GSE267535 | GEO | 2025/09/17

REPOSITORIES: GEO

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Similar Datasets

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

Project description:Triple-negative breast cancer (TNBC) is the most aggressive form of BC and despite improvements in neoadjuvant treatment with immune checkpoint blockade (ICB) targeting PD-1, response rates vary, and patients relapse with metastatic disease. Using human samples and mouse models, we show that myeloid cells, particularly monocytes, increase in aggressive TNBC draining lymph nodes (TDLN) showing T-cell suppressive capacity via PD-L1 and iNOS. Tumor-induced TLR4 ligands reprogrammed TDLN fibroblastic reticular cells (FRCs) through TLR4 activation to induce the recruitment of monocytes via CCL2 and CCL7 in vascularized and T-cell areas. Indeed, monocytes expressing the receptor of CCL2/7 CCR2 home to and colocalize with FRC-rich niches. The local inhibition of this recruitment axis at the TDLN site, either through CCR2 or TLR4 inhibition, in combination with PD-1 blocking, resulted in reduced LN and distant lung metastasis in mouse models. A subset of TNBC patients with worse survival was stratified using TLR4 ligands, including TNC, S100A9, and FN1. Our results thus demonstrate a novel mechanism through which metastatic TNBC tumors reprogram the TDLN-niche to facilitate PD-L1-mediated immune evasion that precedes and drives metastasis. We thereby provide an opportunity to improve the efficacy of ICB in TNBC patients and to use the TDLN or our primary tumor signature as predictive biomarkers.

2025-09-17 | GSE267534 | GEO

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

2025-09-17 | GSE267533 | GEO

SPP1+ Neutrophils Mediate Resistance to lmmune Checkpoint Blockade in BAP1-Inactivated Tumors

Project description:BAP1 inactivation, observed across multiple human cancers, is linked to immune checkpoint blockade (ICB) resistance and adverse clinical outcomes. The mechanisms underlying BAP1-associated ICB sensitivity could provide potential targets to enhance ICB efficacy. Here, we showed that BAP1 inactivation fosters an immunosuppressive tumor microenvironment (TME), marked by increased infiltration of M2-like macrophages and neutrophils. Single-cell transcriptomic analysis revealed an expansion of SPP1+ neutrophils in ICB-treated, BAP1-inactivated tumors. These SPP1+ neutrophils displayed a pro-tumorigenic phenotype and conferred resistance to anti-PD-1 therapy by engaging with cytotoxic T cells via PD-1/PD-L1 signaling. Notably, depletion of neutrophils, but not macrophages, restored sensitivity to ICB in BAP1-inactivated tumors. Mechanistically, BAP1 loss significantly increased CCL2 secretion, driving neutrophil SPP1+ polarization, delaying neutrophil apoptosis, and promoting ICB resistance. This resistance could be significantly mitigated by targeting the CCL2-CCR2 axis. These results underscore the role of BAP1 in modulating the immune landscape and suggest that targeting CCL2-CCR2-mediated neutrophil polarization may overcome ICB resistance in BAP1-inactivated tumors.

2025-09-03 | GSE284219 | GEO

Phosphoproteomic Characterization of Signaling Networks Resulting from Activation of Chemokine Receptor CCR2

Project description:Leukocyte recruitment, a universal feature of tissue inflammation, is regulated by the interactions of chemokines with their G protein-coupled receptors. Activation of CC chemokine receptor 2 (CCR2) by its cognate chemokine ligands, including CCL2, plays a central role in recruitment of monocytes in several inflammatory diseases. In this study, we used phosphoproteomics to enable unbiased characterization of the signaling network resulting from CCL2 activation of CCR2. Using data-independent acquisition (DIA) mass spectrometry, both the proteome and phosphoproteome were quantified for FlpIn-HEK293T cells stably expressing CCR2, at six time points after activation with CCL2, in comparison with untreated cells. Differential expression analysis identified 699 significantly regulated phosphorylation sites located on 441 proteins. As expected, many of these proteins participate in canonical signal transduction pathways and the regulation of actin cytoskeleton dynamics, including numerous guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). In addition, we identified regulated phosphorylation sites in numerous proteins that exert functions in the nucleus, including several constituents of the nuclear pore complex. This study provides an unprecedented level of detail about CCR2 signalling and identifies potential novel targets for regulation of CCR2 function.

2020-04-08 | PXD015845 | Pride

Expression data from S100A9 and HMGB1 treated human CD14+ monocytes

Project description:TLR4 signaling was reported to be involved in the upregulation of PD-L1 expression and induction of immunosuppressive properties of human CD14+ monocytes. Damage associated molecular patterns (DAMPs) S100A8, A9, and HMGB1, which act as endogenous TLR4 ligands, drive MDSC activation and were shown to be markedly expressed in the tumor microenvironment (TME) of solid tumors. The role of S100A8/9 and HMGB1 in the acquisition of MDSC immunosuppressive activity remains to be better defined.

2024-07-19 | GSE254271 | GEO

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node [scRNA-Seq]

Project description:Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a TCF-1+ PD-1+ CD8+ stem-like T cell subset in the tumor-draining lymph node (TdLN). We found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. We also found that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.

2024-02-22 | GSE256178 | GEO

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node [TCR-Seq]

2025-03-14 | GSE291835 | GEO

Gene expression profiles of mouse monocytes deficient in the CCL2/CCR2 chemokine signaling

Project description:Gene-level transcriptome analysis of monocyte mRNA derived from mice that are genetically deficient of the Ccl2 gene or Ccr2 gene The CCL2/CCR2 chemokine axis is critical in monocytes mobilization and innate immunity. Although mice deficient in either gene manifest similar phenotype, such as reduced atherosclerosis, some biologic processes are disrupted in starkly different ways in these mice. We found in a Her2/neu driven mammary carcinoma model, the absence of Ccl2 inhibits tumor growth and prolongs survival, while genetic deletion of Ccr2 has the opposite effect. One of the postulated mechanisms is that Ccl2 and Ccr2 affect monocyte development in different manners. This experiment was designed to compare the whole transcriptome of monocytes that are deficient in either Ccl2 or Ccr2, with the hypothesis that differential development of these monocytes will manifest as differential gene expression profiles.

2016-10-21 | GSE88962 | GEO

Different PD-L1 Assays Reveal Distinct Immunobiology and Clinical Outcomes in Urothelial Cancer

Project description:Testing for PD-L1 expression by immunohistochemistry (IHC) is used to predict immune checkpoint blockade (ICB) benefit but has performed inconsistently in urothelial cancer (UC) clinical trials. Different approaches are used for PD-L1 IHC. We analyzed paired PD-L1 IHC data on UC samples using the SP142 and 22C3 assays from the phase 3 IMvigor130 trial and found discordant findings summarized by four phenotypes: PD-L1 positive by both assays (PD-L1 double positive; PD-L1DP), PD-L1 positive by the SP142 assay only (SP142 single positive; SP142SP), PD-L1 positive by the 22C3 assay only (22C3 single positive; 22C3SP), and PD-L1 negative by both assays double negative (PD-L1 double negative; PD-L1DN). PD-L1DP and SP142SP UCs were associated with more favorable ICB outcomes and increased dendritic-cell (DC) infiltration. SP142 PD-L1 staining co-localized with DC-LAMP, a DC marker, while 22C3 staining was more diffuse. 22C3SP UCs, associated with worse outcomes, were enriched in tumor cell–dominant PD-L1 expression. Multiplex IHC in an independent ICB-treated cohort confirmed that tumor cell–dominant PD-L1 expression was associated with shorter survival. Using different PD-L1 assays, we uncovered that SP142 may preferentially stain PD-L1–expressing DCs, key to orchestrating antitumor immunity, while tumor cell–dominant PD-L1 expression, which underlyies a subset of “PD-L1 positive” specimens, is associated with poor ICB outcomes.

2025-01-17 | GSE286455 | GEO

Next Generation Sequencing of tumor tissue (4T1 cell) of BALB/c

Project description:Immune checkpoint blockade (ICB), particularly programmed death 1 (PD-1) and its ligand (PD-L1), has shown considerable clinical benefits in patients with various cancers. Many studies show that PD-L1 expression may be biomarkers to help select responders for anti-PD-1 treatment. Therefore, it is necessary to elucidate the molecular mechanisms that control PD-L1 expression. As a potential chemosensitizer and anticancer drug, copper combined with disulfiram (DSF) kills tumor cells by regulating multiple signaling pathways and transcription factors in vitro and in vivo. Here, we showed that DSF increased PD-L1 expression in triple negative breast cancer (TNBC) cells. Through TCGA data analysis, we found that DNMT1 and IRF7 were highly expressed and the hypermethylation states in the IRF7 gene body promoter region in TNBC vs normal breast tissue (NBT). Then, we demonstrated that DSF affected PD-L1 expression via DNMT1-mediated IRF7 hypomethylation in two TNBC cell lines. In vivo experiments, DSF significantly enhanced the response to PD-1 antibody (Ab) in the triple-negative 4T1 BC mouse model. By analyzing the results of the tumor tissue sequencing, the DSF joint anti-PD-1 Ab could be a significant activation of anti-tumor immunity. And the inactive state of immune associated pathways was found to be reversed, such as Th1 and Th2 cell differentiation, antigen processing and presentation, natural killer cell-mediated cytotoxicity and T cell receptor signal transduction. In conclusion, we found that DSF could up-regulate PD-L1 in TNBC cells and elucidated its mechanism. Our findings revealed that the combination of DSF and anti-PD-1 Ab could activate the tumor immune microenvironment (TIME) to show much better antitumor efficacy than monotherapy.

2021-11-05 | GSE186885 | GEO

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