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  • Review Article
  • Published:

Tumour–induced immune modulation of sentinel lymph nodes

Key Points

  • In most patients with melanoma who develop metastases, the regional lymph nodes are the first organs to be affected.

  • The techniques of lymphatic mapping and sentinel-node biopsy (LM/SNB) can identify and localize the sentinel lymph node (SLN), which is the lymph node at greatest risk for early metastases.

  • As the first lymph node to receive lymph from the primary melanoma, the SLN is maximally exposed to tumour-derived bioactive molecules and is therefore an excellent model for the study of interactions between the tumour and lymphoid tissue.

  • We postulate that the susceptibility of SLNs to metastases is due, in part, to the modulation of lymph-node function by tumour products.

  • Studies have shown that down-regulation of the immune function of SLNs might underlie their susceptibility to metastases.

  • These alterations affect the influx of T cells to the SLN and the crucial interactions of T cells with paracortical dendritic cells for antigen presentation.

  • Cytokines can reverse the down-regulation of immune-cell number and activity in the SLN, and cytokine administration might be a new approach to adjuvant therapy to prevent and reverse lymph-node metastases.

Abstract

Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.

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Figure 1: Routes of metastasis from primary melanoma.
Figure 2: Strength of the immune reaction in individual regional lymph nodes oriented relative to a primary tumour or to a lymph-node metastasis.
Figure 3: Passage of tumour cells, blue dye and carbon particles to and through sentinel lymph nodes.
Figure 4: Variations in dendritic-cell frequency, density and maturation phenotype in sentinel and non-sentinel lymph nodes.
Figure 5: Changes in the density, dendritic complexity and interactivity of paracortical dendritic cells in sentinel and non-sentinel lymph nodes.

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Acknowledgements

We thank D. L. Morton for his long-standing and continued interest in these studies and G. Berry at the John Wayne Cancer Institute, Santa Monica, California, who provided skilled editorial support.

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Correspondence to Alistair J. Cochran.

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Glossary

Metastases

Colonies of malignant tumour cells that move (in most cases) through the lymphatic or blood vessels to tissues remote from the site of the primary tumour and grow there expansively.

Lymphoscintigraphy

A nuclear-medicine technique in which a radioisotope is injected intradermally at the site of a primary tumour and the spread of radioactivity is observed to detect the lymphatic drainage and the site of the sentinel lymph node(s).

Soil and seed hypothesis

The widely held view that for tumour cells to establish as metastases, they (the seed) must acquire specific characteristics that aid their survival in non-native tissue, and the host tissue (the soil) must be altered in ways that make it susceptible to tumour-cell implantation and growth.

Veiled cells

Dendritic cells (Langerhans cells) in the afferent lymph that transport antigens from the skin to the lymph node. During transport, the dendrites of these cells are withdrawn, and layered, veil-like membranous structures are established.

Neoplasm

Literally means 'new growth', but is conventionally used in medicine to describe the proliferation of (usually) one type of cell that, in most cases, creates a defined tissue swelling or tumour. Benign neoplasms expand at their site of origin but do not spread to tissues remote from this site. By contrast, malignant neoplasms spread (metastasize) to tissues remote from their origin.

T helper cells

(TH cells). At least two distinct subsets of activated CD4+ T cells have been described. TH1 cells produce interferon-γ, lymphotoxin and tumour-necrosis factor, and support cell-mediated immunity. TH2 cells produce interleukin-4 (IL-4), IL-5 and IL-13, support humoral immunity, and downregulate TH1-cell responses.

Concanavalin A

A plant lectin that functions as a T-cell mitogen.

High endothelial venules

(HEVs). Venules (small veins that join capillaries to larger veins) that have a high-profile endothelium and are present in the paracortex of lymph nodes and tonsils, as well as in the interfollicular areas of Peyer's patches. HEVs are important for lymphocyte homing to secondary lymphoid organs.

Fascin

A 54–58 kDa monomeric actin-filament-bundling protein. Fascin crosslinks F-actin into highly ordered bundles in dynamic cell extensions.

Plasmacytoid DCs

A subset of dendritic cells (DCs) that were described first in humans and termed plasmacytoid because of their microscopic appearance, which is similar to plasmablasts. In humans, these DCs can be derived from lineage-negative stem cells in peripheral blood and are the main producers of type I interferon (IFN) in response to virus infections. Recent studies have identified a subset of type I IFN-producing DCs in mice, which are characterized by expression of B220 and Ly6C.

ELISPOT

An antibody-capture-based method for enumerating specific T cells (CD4+ and CD8+) that secrete a particular cytokine (often interferon-γ).

B16 melanoma

A widely used experimental mouse melanoma that usually grows in C57BL/6 mice.

Adjuvant

An agent mixed with an antigen that increases the immune response to that antigen after immunization.

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Cochran, A., Huang, RR., Lee, J. et al. Tumour–induced immune modulation of sentinel lymph nodes. Nat Rev Immunol 6, 659–670 (2006). https://doi.org/10.1038/nri1919

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