Lymph-node metastasis is a prognosis factor for poor clinical outcome of breast cancer patients. Currently, how breast cancer cells establish pre-metastatic niche in the tumor-draining lymph nodes (TDLNs) is still unclear. To address this question, we isolated heterogeneous cells including immune and stromal cells from naive lymph nodes (LNs) of the FVB/NJ mice and TDLNs of the MMTV-PyMT mice. Single-cell RNA sequencing was performed to investigate the transcriptome of the cells and various bioinformatics analyses were used to identify the altered pathways. Our results revealed several significant changes between naïve LNs and TDLNs. First, according to immunologic signature and pathway analysis, CD4+ and CD8 + T cells showed upregulated angiogenesis pathway genes and higher regulatory T (Treg)-associated genes while they demonstrated downregulation of interferon response and inflammatory response gene signatures, concurrently suggesting an immunosuppressive microenvironment in the TDLNs. Second, profiling of B cells showed down-regulation of marginal zone B lymphocytes in the TDLNs, which was validated by flow cytometric analysis. Third, we found the enhancement of oxidative phosphorylation pathway in the fibroblastic reticular cells (FRCs) of the MMTV-PyMT mice and the elevation of related genes including Prdx3, Ndufa4 and Uqcrb, suggesting massive ATP consumption and TCA cycle metabolism in the FRCs. Collectively, our results reveal the reprogramming of TDLNs during breast cancer progression at single-cell level in a spontaneous breast cancer model and suggest the changes in immune modulation and metabolic switch are key alterations in the preparation of pre-metastatic niche by breast cancer cells.
Metastasis is a major cause of death in patients with cancer. The two main routes for cancer cell dissemination are the blood and lymphatic systems. The underlying mechanism of hematogenous metastasis has been well characterized in the past few decades. However, our understanding of the molecular basis of lymphatic metastasis remains at a premature stage. Conceptually, cancer cells invade into lymphatic capillary, passively move to collecting lymphatic vessels, migrate into sentinel lymph node (SLN;, the first lymph node to which cancer cells spread from the primary tumor), and enter the blood circulatory system via the subclavian vein. Before arriving, cancer cells release specific soluble factors to modulate the microenvironment in SLN to establish a beachhead for successful colonization. After colonization, cancer cells inhibit anti-tumor immunity by inducing the recruitment of regulatory T cell and myeloid-derived suppressor cells, suppressing the function of dendritic cell and CD8+ T cell, and promoting the release of immunosuppressive cytokines. The development of novel strategies to reverse cancer cell-triggered SLN remodeling may re-activate immunity to reduce beachhead buildup and distant metastasis. In addition to being a microanatomic location for metastasis, the SLN is also an important site for immune modulation. Nanotechnology-based approaches to deliver lymph node-tropic antibodies or drug-conjugated nanoparticles to kill cancer cells on site are a new direction for cancer treatment. Conversely, the induction of stronger immunity by promoting antigen presentation in lymph nodes provides an alternate way to enhance the efficacy of immune checkpoint therapy and cancer vaccine. In this review article, we summarize recent findings on the reprogramming of SLN during lymphatic invasion and discuss the possibility of inhibiting tumor metastasis and eliciting anti-tumor immunity by targeting SLN.
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