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Tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. A novel cancer metastasis pathway That tumorigenesis can be closely linked to an inflammatory microenvironment has been well established. In a new study, Karin de Visser and colleagues estimate the more systemic inflammatory effects observed in a mouse model of breast cancer. They find that interleukin (IL)-1β expression in tumours elicits IL-17 expression in γδ T cells at a local level, which through granulocyte colony-stimulating factor production promotes systemic accumulation of neutrophils in multiple organs. Interfering with this cascade of events, for example at the level of neutrophil activation, reduces lung and lymph node metastases in this breast cancer model. These findings illustrate the perhaps wider than anticipated systemic effects elicited by localized tumours, at the same time offering multiple points of potential therapeutic interference. Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation 1 , 2 . However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanistically demonstrate that interleukin (IL)-1β elicits IL-17 expression from gamma delta (γδ) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. Neutralization of IL-17 or G-CSF and absence of γδ T cells prevents neutrophil accumulation and downregulates the T-cell-suppressive phenotype of neutrophils. Moreover, the absence of γδ T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system—the γδ T cell/IL-17/neutrophil axis—represents a new strategy to inhibit metastatic disease.

Malignant tumors release growth factors such as VEGF-C to induce lymphatic vessel expansion (lymphangiogenesis) in primary tumors and in draining sentinel LNs, thereby promoting LN metastasis. Surprising recent evidence suggests that lymphatic vessels do not merely represent passive channels for tumor spread, but that they may actively promote tumor cell recruitment to LNs, cancer stem cell survival, and immune modulation. New imaging approaches allow the sensitive visualization of the earliest LN metastases and the quantitative, noninvasive measurement of the function of tumor-draining lymphatic vessels, with potential applications in the development of biomarkers for prognosis and measurement of therapeutic response.

Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, and that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic signature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy. Tumor-draining lymph nodes are often the first site of metastasis in breast cancer patients. Here, the authors show that metastatic lymph nodes are characterized by the accumulation of suppressive regulatory T cells with a distinct phenotype compared to matched non-invaded lymph nodes and tumors.

Cancer dissemination to lymph nodes (LN) is associated with a worse prognosis, increased incidence of distant metastases and reduced response to therapy. The LN microenvironment puts selective pressure on cancer cells, creating cells that can survive in LN as well as providing survival advantages for distant metastatic spread. Additionally, the presence of cancer cells leads to an immunosuppressive LN microenvironment, favoring the evasion of anti-cancer immune surveillance. However, recent studies have also characterized previously unrecognized roles for tumor-draining lymph nodes (TDLNs) in cancer immunotherapy response, including acting as a reservoir for pre-exhausted CD8+ T cells and stem-like CD8+ T cells. In this review, we will discuss the spread of cancer cells through the lymphatic system, the roles of TDLNs in metastasis and anti-cancer immune responses, and the therapeutic opportunities and challenges in targeting LN metastasis.

Tumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated with cancer progression. Here, we used the ret transgenic spontaneous murine melanoma model that mimics human melanoma. Skin tumors and metastatic lymph nodes showed increased levels of inflammatory factors such as IL-1β, GM-CSF, and IFN-γ, which correlated with tumor progression. Moreover, Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs), known to inhibit tumor reactive T cells, were enriched in melanoma lesions and lymphatic organs during tumor progression. MDSC infiltration was associated with a strong TCR ζ-chain down-regulation in all T cells. Coculturing normal splenocytes with tumor-derived MDSC induced a decreased T-cell proliferation and ζ-chain expression, verifying the MDSC immunosuppressive function and suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of sildenafil beneficial outcome, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.

Background Lymph node metastasis is more likely in early-stage breast cancer with lower tumor-infiltrating lymphocyte (TIL) density. Therefore, we investigated the correlation between TILs and lymph node metastasis in cT1 breast cancer patients undergoing surgery and the usefulness of TILs in predicting sentinel lymph node metastasis (SLNM) in cT1N0M0 breast cancer. Methods We investigated 332 breast cancer patients who underwent surgery as the first-line treatment after preoperative diagnosis of cT1. A positive diagnosis of SLNM as an indication for axillary clearance was defined as macrometastasis in the sentinel lymph node (SLN) (macrometastasis: tumor diameter > 2 mm). Semi-quantitative evaluation of lymphocytes infiltrating the peritumoral stroma as TILs in primary tumor biopsy specimens prior to treatment was conducted. Results For SLN biopsy (SLNB), a median of 2 (range, 1–8) SLNs were pathologically evaluated. Sixty cases (19.4%) of SLNM (macrometastasis: 46, micrometastasis: 16) were observed. Metastasis was significantly greater in breast cancers with tumor diameter > 10 mm than in those with diameter ≤ 10 mm (p = 0.016). Metastasis was significantly associated with lymphatic invasion (p < 0.001). These two clinicopathological factors correlated with SLNM even in patients diagnosed with cN0 (tumor size; p = 0.017, lymphatic invasion; p = 0.002). Multivariate analysis for SLNM predictors revealed lymphatic invasion (p = 0.008, odds ratio [OR] = 2.522) and TILs (p < 0.001, OR = 0.137) as independent factors. Conclusions Our results suggest a correlation between lymph node metastasis and tumor immune-microenvironment in cT1 breast cancer. TIL density may be a predictor of SLNM in breast cancer without lymph node metastasis on preoperative imaging.

The recurrence and metastasis of breast cancer limit the effectiveness of clinical treatments, making them important issues for clinicians to address. Tumor-associated macrophages (TAMs) contribute to regulating the immune system. C-C motif chemokine ligand 5 (CCL5) is an inflammatory chemokine that promotes chemotaxis on cells involved in the immune/inflammatory response. Breast cancer cells that secrete CCL5 act on THP-1 cells, influencing the invasion and metastasis of tumors. However, knowledge remains limited regarding the mechanism underlying the effects of CCL5 on breast cancer cells and TAMs, as well as the mechanisms promoting the migration and invasion of breast cancer. The present study demonstrated that the positive expression of CCL5 was associated with lymph node status and tumor-node-metastasis stage. Treatment with ≥20 ng/ml CCL5 significantly promoted the migration and invasion of MCF-7 and MDA-MB-231 cells. CCL5-small interfering RNA intervention significantly decreased the migration and invasion of the two cell types. In vitro, THP-1 cells were successfully induced to become TAMs, which were then recruited via the chemotactic effects of CCL5. This process was achieved through the co-stimulation of phorbol-12-myristate-13- acetate, interleukin-4 (IL-4) and IL-13. The nuclear factor-κB (NF-κB) signaling pathway was activated to regulate EMT, as well as the migration and invasion process of MCF-7 cells, when co-cultured with TAMs. We also reported that blocking the expression of CCL5 in vivo may significantly inhibit the growth of human breast cancer xenografts. Therefore, targeting CCL5 may be considered as a novel therapeutic strategy for suppressing the invasion and metastasis of breast cancer.

Background In clinical practice, lymph node status has an important impact on colon cancer (CC) management and treatment. The role of the tumor microenvironment collagen score and immunoscore in colon cancer lymph node metastasis remains unknown. Methods A total of 249 CC patients who underwent laparoscopic-assisted D3 lymphadenectomy from June 2016 to May 2019 were included. The patients’ clinicopathological data were collected retrospectively. A total of 142 collagen features were extracted by multiphoton imaging and collagen quantification. A collagen score was constructed using a LASSO logistic regression model. Antibodies against CD3 and CD8 were used for immunostaining. The immunoscore was constructed based on the mean densities of CD3 + and CD8 + T cells both in the tumor center and invasion margin on imaging. Results The lymph node metastasis rate among colon cancer patients was 42.2% (105/249). The multivariate analysis indicated that lymphatic invasion (OR: 3.892, 95% CI: 1.784–8.491, p  = 0.001), vascular invasion (OR, 3.234, 95% CI: 1.544–6.776);  p  = 0.002), mucus adenocarcinoma and signet-ring cell carcinoma (OR: 2.990, 95% CI: 1.413–6.328, p  = 0.004), the collagen score (OR: 6.304, 95% CI: 2.145–18.527,  p  = 0.001) and the immunoscore [intermediate group (OR, 2.473; 95% CI, 1.192–5.130; p  = 0.015); low group (OR, 5.877; 95% CI, 2.423–14.257; p  < 0.01)] were independent risk factors for colon cancer lymph node metastasis. The newly developed model comprising these five independent predictors showed good discrimination with an AUROC of 0.809 (95% CI: 0.755–0.862). The new model performed significantly better than the traditional clinicopathological model [AUROC: 0.715 (95% CI: 0.649–0.780), p  < 0.001]. Conclusions The tumor microenvironment collagen score and immunoscore are associated with colon cancer lymph node metastasis.

Infiltration of resident memory T cells (TRMs) in the main tumor has been reported as a favorable prognostic factor. However, the role of TRMs in the lymph nodes (LNs) remains unclear. Thus, we examined the prognostic impact of TRMs infiltration within LNs of patients with gastric cancer (GC). Among 151 patients with metastasis to LN station No. 3, we classified them into two groups (CD103hi and CD103lo) based on the number of CD103+ T cells using immunohistochemical staining and analyzed the association between these groups and survival outcomes. We also examined the phenotype of CD8+ CD103+ T cells in the metastatic LNs using flow cytometry. Among patients with LN metastasis, metastasis to LN station No. 3 was significantly associated with a poor prognosis. There was a significant correlation between the number of CD8+ CD103+ T cells between the main lesion and the metastatic LNs. CD103hi was associated with a favorable prognosis (5‐year overall survival [OS], log‐rank p = 0.001; 5‐year recurrence free survival [RFS], log‐rank p = 0.001). Among adjuvant chemotherapy cases, patients with CD103hi exhibited significantly better OS and RFS than those with CD103lo (OS, log‐rank p < 0.001; RFS, log‐rank p < 0.001). Flow cytometry revealed that PD‐1 expression in CD8+ CD103+ T cells was higher in metastatic than in normal LNs. Among patients with CD103hi, those with high PD‐1 expression exhibited significantly better OS than those with low PD‐1 expression. In conclusion, the infiltration of TRMs into LNs is a critical prognostic factor in GC. The role of resident memory T cells (TRM) in the lymph nodes remains unclear. Thus, we examined the prognostic impact of TRM cell infiltration in lymph nodes among gastric cancer patients with lymph node metastasis. As a result, we revealed that the infiltration of TRM cells into lymph nodes is a significant prognostic factor both in resected and adjuvant cases.

Lymph node metastasis is a pivotal determinant of prognosis in lung adenocarcinoma, yet its impact on tumour microenvironment remodelling remains insufficiently characterised. In this study, we employed single‐cell RNA sequencing to compare metastatic and non‐metastatic lymph nodes, delineating metastasis‐associated immune and stromal alterations. Metastatic nodes exhibited marked reductions in dendritic cell and T cell infiltration alongside increases in monocytes and SPP1+ macrophages, indicative of an immunosuppressive milieu. Intercellular communication analysis revealed strengthened interactions among SPP1+ macrophages, monocytes, and epithelial cells, suggesting coordinated signalling that may further enforce immune suppression. Integrating differentially expressed genes with multi‐omic features, we developed an ensemble machine learning model, LNRScore, which robustly stratified patients into distinct risk groups. A high LNRScore was associated with poorer prognosis and reduced immune infiltration, whereas a low LNRScore correlated with higher immunogenicity and greater predicted responsiveness to immunotherapy based on TCIA assessments. Further analyses identified HMGA1 as a core gene within the model, closely linked to adverse outcomes; functional assays demonstrated that high HMGA1 expression promotes the proliferation and migration of the LLC cell line, supporting its role in metastatic progression. Collectively, this study defines the immune microenvironmental remodelling associated with lymph node metastasis, establishes an effective risk prediction model (LNRScore), and highlights HMGA1 as a potential target for precision diagnosis and therapy in lung adenocarcinoma.