Neutrophil diversity and plasticity in tumour progression and therapy

Abstract

Neutrophils play a key role in defence against infection and in the activation and regulation of innate and adaptive immunity. In cancer, tumour-associated neutrophils (TANs) have emerged as an important component of the tumour microenvironment. Here, they can exert dual functions. TANs can be part of tumour-promoting inflammation by driving angiogenesis, extracellular matrix remodelling, metastasis and immunosuppression. Conversely, neutrophils can also mediate antitumour responses by direct killing of tumour cells and by participating in cellular networks that mediate antitumour resistance. Neutrophil diversity and plasticity underlie the dual potential of TANs in the tumour microenvironment. Myeloid checkpoints as well as the tumour and tissue contexture shape neutrophil function in response to conventional therapies and immunotherapy. We surmise that neutrophils can provide tools to tailor current immunotherapy strategies and pave the way to myeloid cell-centred therapeutic strategies, which would be complementary to current approaches.

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Fig. 1: Neutrophils in tumour promotion.
Fig. 2: Antitumour potential of neutrophils.
Fig. 3: Therapeutic targeting of neutrophils.

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Acknowledgements

Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (PRIN 2015YYKPNN to A. M., PRIN 2017K7FSYB to S. J. and PRIN 20177J4E75 to R. B.), Ministero della Salute (GR-2016-02361263 to S. J. and GR-2016-02363531 to D. D. M.) and Fondazione AIRC per la ricerca sul cancro (AIRC IG-19014 to A. M., AIRC IG-22815 to S. J., AIRC IG-20269 to R. B. and AIRC Start-Up grant-19141 to D. D. M.) are acknowledged. A. P. is the recipient of a fellowship from Fondazione Umberto Veronesi (FUV).

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S. J., A. P., D. D. M., A. S., R. B. and A. M. all researched the data for the article. S. J., R. B. and A. M. provided substantial contributions to discussions of the content. S. J., A. P., D. D. M., A. S., R. B. and A. M. all contributed equally to writing the article. S. J., R. B. and A. M. reviewed and/or edited of the manuscript before submission.

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Correspondence to Sebastien Jaillon or Alberto Mantovani.

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Nature Reviews Cancer thanks A. Hidalgo, Z. Granot and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Neutrophilia

An increase in the absolute number of peripheral blood neutrophils compared with the control value.

Oxysterols

Cholesterol metabolites involved in cholesterol homeostasis and immune and inflammatory responses. Oxysterols interact with the transcription factor liver X receptor (LXR) and the G protein-coupled receptors CXC-chemokine receptor 2 (CXCR2) and Epstein–Barr virus-induced G protein-coupled receptor 2 (EBI2).

Anaphylatoxin

A protein fragment (C3a and C5a) produced by cleavage of the complement components C3 and C5. Anaphylatoxins bind G protein-coupled receptors expressed on myeloid cells and are potent chemotactic agents.

Atypical chemokine receptor 2

(ACKR2). A seven-transmembrane receptor belonging to the chemokine receptor family that lacks a DRY motif and does not mediate chemotaxis (directional cell migration) but regulates chemokine bioavailability by scavenging, transcytosis or presentation of the ligand.

Pattern recognition receptors

Germline-encoded host sensors that recognize essential molecules expressed by microorganisms. Signalling through these receptors drives initiation of the inflammation, innate and adaptive responses.

Inflammasome

A multiprotein intracellular complex activated by pathogenic microorganisms and sterile stressors, important for the production of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18.

Neutrophil extracellular traps

(NETs). Networks of extracellular fibres composed of DNA and proteins, such as neutrophil elastase and histones, released from neutrophils upon activation.

Zeitgeber time

(ZT). A standardized unit of time based on a 12-h–12-h light–dark cycle. ZT0 corresponds to the beginning of the light phase and ZT12 to the beginning of the dark phase.

Reactive oxygen species

(ROS). Chemically reactive species containing oxygen that are produced through activation of the NADPH oxidase enzymatic system. ROS have important antimicrobial activity and induce genetic instability.

M1–M2

The extreme ends of a continuum of macrophage polarization states. Classically activated M1 macrophages in response to signals such as interferon-γ (IFNγ) mediate resistance to tumour formation, whereas in response to IL-4 and IL-13 an alternative form of macrophage activation (M2) that mediates tumour promotion is elicited.

N1 and N2

Antitumour neutrophils (N1) and pro-tumour neutrophils (N2). Interferon-β (IFNβ) and transforming growth factor-β (TGFβ) signalling pathways can trigger the formation of N1 and N2 neutrophils, respectively. N1 neutrophils are characterized by a normal density, a hypersegmented nucleus and a cytotoxic activity towards cancer cells, whereas N2 neutrophils have immunosuppressive activity. This classification may represent an oversimplification of neutrophil polarization, activation or maturation states.

Homologous recombination

Genetic recombination in which nucleotides are exchanged between two similar or identical molecules of DNA.

Neutrophil elastase

(NE). A serine protease stored in the neutrophil intracellular granules.

Circulating tumour cells

(CTCs). Cancer cells that have detached from a primary tumour and are found in the bloodstream.

Pre-metastatic niche

An environment in a secondary organ that provides favourable conditions for the seeding of metastatic cells.

Fc receptors

Surface receptors expressed by innate immune cells that recognize the Fc fragment of immunoglobulins. Human and mouse neutrophils express the IgG Fcγ receptors (FcγRs) and human neutrophils express the IgA Fcα receptor I (FcαRI).

Innate lymphoid cells

(ILCs). A group of cells of the innate immune response that belong to the lymphoid lineage and are characterized by a lack of antigen-specific receptors.

Unconventional T cells

(UTCs). A group of T lymphocytes that express the T cell receptor (TCR) αβ or γδ chains and are characterized by a lack of recognition of classical peptide antigens. UTCs include the mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells.

Mass cytometry by time-of-flight

(CyTOF). A flow cytometry platform that utilizes elemental mass spectrometry to detect metal-conjugated antibodies that are bound intracellularly or extracellularly to antigens of interest in single cells.

Undifferentiated pleomorphic sarcoma

(UPS). An aggressive sarcoma of soft tissues or bone that occurs in any part of the body. UPS is characterized by the presence of pleomorphic spindle cells and large atypical cells exhibiting numerous irregular mitoses.

Antibody-dependent cellular cytotoxicity

(ADCC). Lysis of an antibody-coated target cell triggered via the interaction of target-bound antibodies with Fc receptors (FcRs) expressed by effector cells. ADCC can occur through the release of cytotoxic molecules, the expression of cell death-inducing molecules and trogoptosis.

Trogoptosis

A mechanism of cytotoxicity related to trogocytosis mediated by an active process of plasma membrane transfer between interacting cells.

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Jaillon, S., Ponzetta, A., Di Mitri, D. et al. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer 20, 485–503 (2020). https://doi.org/10.1038/s41568-020-0281-y

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