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Lymphatic vessels in the age of cancer immunotherapy

Nature Reviews Cancer (2024)Cite this article

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Abstract

Lymphatic transport maintains homeostatic health and is necessary for immune surveillance, and yet lymphatic growth is often associated with solid tumour development and dissemination. Although tumour-associated lymphatic remodelling and growth were initially presumed to simply expand a passive route for regional metastasis, emerging research puts lymphatic vessels and their active transport at the interface of metastasis, tumour-associated inflammation and systemic immune surveillance. Here, we discuss active mechanisms through which lymphatic vessels shape their transport function to influence peripheral tissue immunity and the current understanding of how tumour-associated lymphatic vessels may both augment and disrupt antitumour immune surveillance. We end by looking forward to emerging areas of interest in the field of cancer immunotherapy in which lymphatic vessels and their transport function are likely key players: the formation of tertiary lymphoid structures, immune surveillance in the central nervous system, the microbiome, obesity and ageing. The lessons learnt support a working framework that defines the lymphatic system as a key determinant of both local and systemic inflammatory networks and thereby a crucial player in the response to cancer immunotherapy.

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Fig. 1: Antigen and leukocyte transport via the lymphatic vasculature.
Fig. 2: Lymphatic egress contributes to the anatomical compartmentalization of T cell responses.
Fig. 3: Reconciling the paradox of tumour-associated lymphangiogenesis and response to immunotherapy.
Fig. 4: Lymphatic transport and its relationship with the systemic tumour macroenvironment.

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Acknowledgements

T.K. and T.M. contributed equally and are listed alphabetically. The authors thank L.H.M. Geraldo, S. Naik and C. Nowosad for critical reading of the drafted manuscript. T.K. received support from the A.G. Leventis Foundation. A.W.L. is supported by the National Institutes of Health (R01 CA238163, R01 AR080068, U54 CA263001, P50 CA225450), the Department of Defense (ME200052), the Cancer Research Institute (Lloyd J. Old STAR Award), the Mark Foundation for Cancer Research (19-047-ELA), the American Cancer Society (RSG-18-169-01-LIB) and the American Association for Cancer Research (AACR-BMS Midcareer Female Investigator Grant).

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Author notes

  1. These authors contributed equally: Triantafyllia Karakousi, Tenny Mudianto.

Authors and Affiliations

  1. Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, USA

    Triantafyllia Karakousi, Tenny Mudianto & Amanda W. Lund

  2. Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA

    Amanda W. Lund

  3. Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA

    Amanda W. Lund

Authors
  1. Triantafyllia Karakousi
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The authors contributed equally to all aspects of the article.

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Correspondence to Amanda W. Lund.

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A.W.L. reports consulting services for AGS Therapeutics. T.K. and T.M. declare no competing interests.

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Nature Reviews Cancer thanks Sirpa Jalkanen, Steven Stacker, who co-reviewed with Rae Farnsworth, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Chylous effusion

A medical condition in which lymph formed in the digestive system (chyle) leaks and accumulates into body cavities owing to a blockage in lymphatic drainage.

Egress

The directional and active migration of leukocytes out of tissues, lymphoid and non-lymphoid, through the efferent lymphatic vasculature.

Glymphatic system

A waste clearance system in the brain of vertebrates that uses perivascular channels formed by astroglial cells to promote the transport of macromolecules from the CNS.

High endothelial venules

Specialized blood vessels found in lymphoid organs that are crucial to facilitate lymphocyte migration to lymphoid tissues.

Interstitial flows

The slow movements of fluid through the extracellular matrix in connective tissues between blood and lymphatic vessels. Increases with inflammation as a function of vascular leakiness.

Intestinal lacteal

Specialized lymphatic vessels found in the small intestine that are crucial in the absorption of dietary fats and fat-soluble molecules.

LN paracortex

The inner area of the LN cortex between the outer cortex, which contains the B cell follicles, and the medulla. This area is rich in T lymphocytes and antigen-presenting cells (APCs).

Lymphadenectomy

A surgical procedure to remove one or more lymph nodes. Often used as an important part of cancer staging and treatment.

Lymphangiocrine factors

Molecules produced by lymphatic endothelial cells that can stimulate organ-specific repair activities in damaged or diseased organs.

Lymphangiogenesis

A process of lymphatic growth in which new vessels form from the proliferation of pre-existing vessels.

Lymphangiography

An imaging technique that leverages the uptake of interstitial dyes to image lymphatic structures and their functional transport to lymph nodes.

Lymphatic remodelling

The reorganization, dilation, activation or growth of the lymphatic vasculature.

Lymphedema

A chronic condition characterized by swelling and interstitial fluid accumulation owing to impaired lymphatic drainage.

Lymph node

(LN). Secondary lymphoid organs that are linked by lymphatic vessels, provide an anatomical structure for the accumulation of T and B cells and perform important immune surveillance functions. Lymph node structure is maintained by a network of specialized non-haematopoietic cells, including lymphatic endothelial cells, that compartmentalize and distribute cells, antigens and activating signals for proper immune function. Lymph nodes are also often first sites of metastasis.

Mesentery

In the small intestine, a fan-shaped membrane that attaches the jejunum and ileum to the posterior abdominal wall. The mesentery helps store fat and facilitates blood and lymphatic connections to the intestines.

Neoadjuvant therapy

The therapeutic administration of a drug or treatment given before definitive surgical therapy.

Sentinel lymph node

(SLN). A clinical term to define the first lymph node draining the tumour as determined by the accumulation of injected radiotracers at the time of surgery (sentinel lymph node biopsy).

Shear stress

A mechanical force that acts in parallel with a surface, in this case referred to as the stresses formed by luminal fluid flow along an endothelial monolayer.

Stem-like T (TSC) cells

Antigen-expanded, TCF1+ T cells with the capacity to maintain persistent T cell responses in the context of chronic antigen, for example, chronic infection, autoimmunity and cancer. Also known as progenitor-exhausted T cells.

Tissue-resident memory T (TRM) cells

A memory T cell state that resides long term in peripheral non-lymphoid and lymphoid tissue and presumably surveys locally for re-encounter with pathogens or neoplastic cells. TRM cells do not recirculate in the absence of additional stimulation and are found in both mouse and human models.

Tumour-draining LNs

A functional term to define any lymph nodes that are connected to and receive direct lymph output from the tumour.

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Karakousi, T., Mudianto, T. & Lund, A.W. Lymphatic vessels in the age of cancer immunotherapy. Nat Rev Cancer (2024). https://doi.org/10.1038/s41568-024-00681-y

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