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Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity

Nature Reviews Cancer volume 12, pages 210–219 (2012)Cite this article

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Abstract

Tumours often engage the lymphatic system in order to invade and metastasize. The tumour-draining lymph node may be an immune-privileged site that protects the tumour from host immunity, and lymph flow that drains tumours is often increased, enhancing communication between the tumour and the sentinel node. In addition to increasing the transport of tumour antigens and regulatory cytokines to the lymph node, increased lymph flow in the tumour margin causes mechanical stress-induced changes in stromal cells that stiffen the matrix and alter the immune microenvironment of the tumour. We propose that synergies between lymphatic drainage and flow-induced mechanotransduction in the stroma promote tumour immune escape by appropriating lymphatic mechanisms of peripheral tolerance.

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Figure 1: Linking mechanobiology, lymphangiogenesis and anti-tumour immunity.
Figure 2: Modelling the biomechanical aspects of the tumour microenvironment in vitro.
Figure 3: Interstitial flow and matrix mechanics manipulate the tumour stroma to promote invasion.
Figure 4: Interstitial flow influences the immune microenvironment in cancer.
Figure 5: Patterns of lymph flow and antigen delivery in the lymph node.

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Acknowledgements

The authors apologize to the many researchers whose work could not be included owing to space constraints. They are grateful to the Swiss National Science Foundation, Swiss Cancer League, European Research Council and the Swiss NCCR in Molecular Oncology for funding.

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  1. Melody A. Swartz and Amanda W. Lund are at the Institute of Bioengineering and Swiss Institute of Experimental Research (ISREC), SV-IBI-LLCB, Station 15, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.,

    Melody A. Swartz & Amanda W. Lund

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Correspondence to Melody A. Swartz.

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Glossary

Cancer-associated fibroblasts

(CAFs). Heterogeneous population of fibroblasts found in the tumour stroma that often exhibit myofibroblast features. They are responsible for stromal stiffening and can lead collective tumour cell invasion.

Dendritic cells

(DCs). The most potent antigen-presenting cells that can activate T cells and thereby induce antigen-specific immune responses.

Fibroblastic reticular cells

(FRCs). Lymph node stromal cells of the paracortical reticular meshwork, a specialized structure that directs the interactions between dendritic cells and T lymphocytes. FRCs express podoplanin (GP38), which is a key component of the reticular meshwork, and secrete cytokines such as CCL21 and CCL19 to attract lymphocytes and maintain their homeostasis. Importantly, FRC features can be exhibited by CAFs, and such lymphoid-like stromal components have been correlated with tumour invasion and metastasis.

Interstitial flow

Fluid flow within the interstitium, driven by pressure gradients between the blood, interstitial and lymphatic compartments. Elevated tumour interstitial fluid pressure or increased lymphatic drainage can cause increased interstitial flow in the tumour stroma.

Interstitial fluid pressure

(IFP). Hydrostatic pressure in the interstitium; it is usually subatmospheric, meaning that excised tissue imbibes water when placed in saline. IFP in solid tumours is often elevated owing to leaky tumour vessels.

Mechanical stress

An applied force per unit area. In tumours, stresses include IFP gradients, shear stresses owing to fluid flow, matrix tension caused by fluid flow or matrix contraction by CAFs, and compressive stresses from a growing tumour pushing on surrounding tissue. Mechanical stress in the extracellular matrix induces mechanical strain according to stiffness.

Myofibroblast

A fibroblast subtype expressing α-smooth muscle actin that displays a contractile, synthetic and pro-fibrotic phenotype. Transforming growth factor-β (TGFβ) both activates, and is activated by, myofibroblasts.

Regulatory T (TReg) cells

FoxP3+ CD4+ T cells that suppress effector T cells and are important for maintaining peripheral tolerance to autoantigens, thereby preventing autoimmunity. Natural TReg cells are educated in the thymus, and inducible TReg cell activation in the periphery requires TGFβ and interleukin-10.

Stromal stiffening

A material property of the tumour stromal extracellular matrix that describes its resistance to deformation under mechanical stress. It can be altered by matrix protein synthesis, collagen crosslinking, matrix alignment and proteolysis.

Tolerance

The process that ensures that B and T cell repertoires are biased against self-reactivity, reducing the likelihood of autoimmunity.

Tumour-associated macrophages

(TAMs). A heterogeneous population of generally immune suppressive, alternatively activated or M2-type macrophages derived from peripheral blood monocytes that are recruited into the tumour mass and that constitute a major component of the immune infiltrate.

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Swartz, M., Lund, A. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat Rev Cancer 12, 210–219 (2012). https://doi.org/10.1038/nrc3186

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