The Multifaceted Effects of Breast Cancer on Tumor-Draining Lymph Nodes

Abstract

Breast cancer (BC) accounts for significant morbidity and mortality among women worldwide. About one in three patients with breast cancer present with lymph node (LN) metastasis and LN status is one of the most important prognostic predictors in patients with BC. In addition to their prognostic value, LNs initiate adaptive immunity against BC. Yet, BC cells often avoid immune-mediated destruction in LNs. This review provides an overview of the ways by which BC cells modulate LN stromal and hematopoietic cells to promote metastasis and immune evasion.

Figure 1

Cellular changes in lymph nodes associated with breast cancer metastases. A: Graphical representation of a normal lymph node. The subcapsular sinus (brown) contains macrophages and is lined by lymphatic endothelial cells. The cortex (blue) contains follicles that consist of B cells and follicular dendritic cells. Fibroblastic reticular cells/conduits are depicted in the cortex and paracortex (green). The paracortex contains T cells, dendritic cells, and high endothelial venules. Macrophages are depicted in the medulla (purple). B: Enlargement of tumor-involved lymph node is seen with the invasion and growth of cancer cells. B cells accumulate in tumor-involved lymph nodes (germinal centers are depicted as darker blue), whereas the overall T cell compartment contracts. Of note, the regulatory T cell population has been shown to expand in tumor-involved lymph nodes. Remodeling of lymph nodes and enhanced collagen production by fibroblastic reticular cells and recruited cancer-associated fibroblasts have been observed in tumor-involved lymph nodes. High endothelial venules are remodeled and show an increased lumen diameter and thinner endothelial layer. In tumor-involved lymph nodes, the lymphatic vasculature is expanded, many dendritic cells are immature, and subsets of functionally impaired natural killer cells and T cells are present. Macrophages, neutrophils, and myeloid-derived suppressor cells are recruited to tumor-involved lymph nodes and exhibit a protumor phenotype. Cancer cells can gain access to lymphatic and blood vasculatures of lymph nodes to further metastasize.

Figure 2

Prometastatic and immune evasion mechanisms in lymph nodes. Inset A: Lymphatic endothelial cells actively recruit breast cancer cells to lymph nodes through chemokines that interact with chemokine receptors on breast cancer cells. Inset B: Cancer cells arrest dendritic cell maturation to limit the priming of antigen-specific T cells in tumor-draining lymph nodes. Inset B: Macrophages, regulatory T cells, myeloid-derived suppressor cells, cancer cells, and B cells (grouped in red boxed area) utilize different mechanisms to likely inhibit (blue symbol) T cell activation and promote T cell and natural killer cell dysfunction (red arrow points to dysfunctional T cells).