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How chemokines organize the tumour microenvironment

Nature Reviews Cancer volume 24, pages 28–50 (2024)Cite this article

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Abstract

For our immune system to contain or eliminate malignant solid tumours, both myeloid and lymphoid haematopoietic cells must not only extravasate from the bloodstream into the tumour tissue but also further migrate to various specialized niches of the tumour microenvironment to functionally interact with each other, with non-haematopoietic stromal cells and, ultimately, with cancer cells. These interactions regulate local immune cell survival, proliferative expansion, differentiation and their execution of pro-tumour or antitumour effector functions, which collectively determine the outcome of spontaneous or therapeutically induced antitumour immune responses. None of these interactions occur randomly but are orchestrated and critically depend on migratory guidance cues provided by chemokines, a large family of chemotactic cytokines, and their receptors. Understanding the functional organization of the tumour immune microenvironment inevitably requires knowledge of the multifaceted roles of chemokines in the recruitment and positioning of its cellular constituents. Gaining such knowledge will not only generate new insights into the mechanisms underlying antitumour immunity or immune tolerance but also inform the development of biomarkers (or ‘biopatterns’) based on spatial tumour tissue analyses, as well as novel strategies to therapeutically engineer immune responses in patients with cancer. Here we will discuss recent observations on the role of chemokines in the tumour microenvironment in the context of our knowledge of their physiological functions in development, homeostasis and antimicrobial responses.

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Fig. 1: Biological response programmes and their chemokines.
Fig. 2: Type 1, 2 and 3 immunity chemokines in the tumour microenvironment.
Fig. 3: Post-translational regulation of chemokines.
Fig. 4: Therapeutic opportunities based on the chemokine system.

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Acknowledgements

This work was supported in part by NIH grants P01-CA240239, R01 AI163223 and R01 AI123349 (to T.R.M.).

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  1. Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Thorsten R. Mempel, Julia K. Lill & Lukas M. Altenburger

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All authors researched data for the article and contributed substantially to discussion of the content. L.M.A. and T.R.M. wrote the article. T.R.M. reviewed and/or edited the manuscript before submission.

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Glossary

Antibody-dependent cellular cytotoxicity

(ADCC). A mechanism through which Fc receptor-expressing immune effector cells, such as NK cells or macrophages, can recognize and kill antibody-coated target cells.

B follicles

Large, well-organized clusters of B cells attracted by CXCL13-expressing mesenchymal cells called follicular dendritic cells and found in secondary lymphoid tissues and tertiary lymphoid structures.

Citrullination

A post-translational protein modification whereby arginine residues are enzymatically converted to citrulline, which can trigger autoimmune reactions against citrullinated proteins, but has also been suggested to alter the function or activity of some proteins, including chemokines.

Cytokine-induced killer cells

A heterogenous population of cells with NK and T cell features generated by ex vivo activation and treatment of peripheral blood mononuclear cells of a patient with cytokines including IL-2, IL-1 and IFNγ.

Diapedesis

The migration of blood-borne leukocytes through the blood vessel wall via interendothelial junctions (paracellular) or through endothelial cells (transcellular) into the surrounding tissue.

Fibroblastic reticular cells

(FRCs). Specialized populations of fibroblast-like mesenchymal cells that provide structure and dynamically organize functional compartments in lymphoid tissues through their interactions with immune cells.

Germinal centre dark zone

The part of the germinal centre where B cells proliferate and hypermutate their B cell receptor genes before again migrating through the light zone, where they are selected for their antigen affinity.

Granulopoiesis

The part of haematopoiesis that leads to the production of neutrophils, eosinophils and basophils.

Haptotactic gradients

Cell motility directed by gradients of immobilized guidance molecules, such as ECM-bound chemokines or adhesion molecules, unlike chemotaxis, where cells follow guidance molecules in solution.

Isotype switching

A genetic mechanism in B cells that changes the immunoglobulin constant region to alter antibody effector function and class, for example, from IgM to IgG.

Leukotrienes

Inflammatory lipid signal molecules produced by white blood cells through oxidative metabolism of the 20-base polymer/oligonucleotide arachidonic acid in their membranes.

Lymph node anlagen

The incipient structures of lymph node organogenesis during embryonic development.

Lymph node interfollicular areas

The lymph node areas between B follicles through which dendritic cells enter lymph nodes and which are occupied by high densities of innate lymphocytes, γδT cells and NKT cells.

Lymph node subcapsular sinus

The lymphatic endothelium-lined space between lymph node capsule and cortex into which afferent lymph and lymph-borne solutes, particles and cells are collected.

Lymphoid-tissue inducer (LTi) cells

A lymphotoxin-producing innate lymphocyte population that stimulates mesenchymal cells to express chemokines and adhesion molecules to promote the formation and expansion of lymph node anlagen.

Lymphoid-tissue organizer (LTo) cells

The lymphotoxin-induced mesenchymal precursors of lymphoid-tissue FRC in lymph node anlagen and other primitive lymphoid tissues.

Necroptosis

A caspase-independent, pro-inflammatory form of programmed cell death.

Neutrophil extracellular traps

(NETs). Fibril matrices composed of chromatin and granule proteins released by neutrophils to entrap and kill extracellular pathogens.

Peyer’s patches

Secondary lymphoid tissues in the antimesenteric wall of the small intestine composed of organized clusters of subepithelial lymphoid follicles.

Single-chain variable fragment

(scFv). Recombinant fusion protein of the light and heavy chain variable regions of an antibody, connected via a linker but lacking antibody constant regions.

Tertiary lymphoid structures

(TLSs). Organized lymphoid tissues that are not developmentally programmed, but arise at sites of chronic inflammation, including tumour microenvironments.

Trans-endocytosis

A molecular process whereby cells use cell surface receptors to bind and remove surface proteins on cells they interact with for internalization and degradation of those target proteins.

Trans-presentation

The mechanism by which cells expressing IL-15, alternative to releasing it as a soluble factor, can express and use the IL-15Rα chain to present this cytokine to cells expressing the IL-15Rβ/γC signalling receptor chains.

Vitiligo

A depigmenting autoimmune disease mediated by T cells that recognize antigens in the melanin synthesis pathway, and a common side effect of effective anti-melanoma immunity.

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Mempel, T.R., Lill, J.K. & Altenburger, L.M. How chemokines organize the tumour microenvironment. Nat Rev Cancer 24, 28–50 (2024). https://doi.org/10.1038/s41568-023-00635-w

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