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Immune crosstalk in cancer progression and metastatic spread: a complex conversation

Abstract

Metastatic disease is responsible for approximately 90% of cancer deaths. For successful dissemination and metastasis, cancer cells must evade detection and destruction by the immune system. This process is enabled by factors secreted by the primary tumour that shape both the intratumoural microenvironment and the systemic immune landscape. Here, we review the evidence of aberrant immune cell crosstalk in metastasis formation and the role that primary tumours play in hijacking these interactions in order to enhance their metastatic potential. Moreover, we highlight the intriguing parallels between the inflammatory pathways underlying inflammatory disorders and cancer progression.

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Fig. 1: T cell priming to tumour antigens and subversion of this process.
Fig. 2: The immunosuppressive tumour microenvironment.
Fig. 3: Systemic inflammation, enabling metastasis.

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Acknowledgements

We apologize to those researchers whose original work could not be cited due to space restrictions. We thank M. Wellenstein and L. Spagnuolo for insightful comments on the manuscript. Research in the De Visser laboratory is funded by a European Research Council Consolidator award (InflaMet 615300), the Dutch Cancer Society (grants KWF10083, KWF10623), the Netherlands Organization for Scientific Research (grant NWO-VICI 91819616), the Oncode Institute and the Beug Foundation for Metastasis Research.

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Correspondence to Karin E. de Visser.

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K.E.d.V. reports research funding from Roche and is a consultant for Third Rock Ventures.

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Glossary

Chronic inflammation

A state of prolonged, abnormal inflammation that is not resolved in the usual way, leading to a progressive change in the immune cell types and polarization states at the site of inflammation.

Immunotherapy

The treatment of disease by activating or suppressing aspects of the immune system. Cancer immunotherapy includes immune checkpoint blockade.

Metastasis

The spread of cancer cells from the primary tumour site to distant organs, via the lymphatics or blood, which they colonize and where they grow into secondary tumours. Different tumour types demonstrate distinct tissue tropisms with regard to where secondary tumours develop, which may be, in part, a consequence of the distinct responses to systemic inflammation by distant tissues.

Premetastatic niche

An environment in a secondary organ that is conducive to the outgrowth of disseminated tumour cells and metastasis formation. Systemic inflammation can contribute to the generation of such an environment.

Tumour microenvironment

In addition to cancer cells, tumours are made up of a number of stromal cells, including immune cells, fibroblasts and endothelial cells, as well as structural components, such as extracellular matrix, and signalling components, including chemokines, cytokines and growth factors.

Immune checkpoint molecules

A series of co-stimulatory or co-inhibitory receptors and their ligands, also referred to as immune checkpoints, that regulate interactions between TCR and MHC complexes. Through this regulation of the strength of antigen-specific T cell activation, immune checkpoint pathways play a critical role in maintaining self-tolerance and minimizing tissue damage.

Polarization

A state of functional activation of a myeloid immune cell in response to specific environmental cues, which can limit or promote disease progression.

Type I interferons

A group of cytokines, the most widely studied of which are IFNα and IFNβ (but which also includes IFNε, IFNτ, IFNκ, IFNω, IFNδ and IFNζ). Type I interferons are best known for their antiviral functions, but they are also known to have anti-neoplastic effects, both through the direct induction of tumour cell death and by stimulating anticancer immune responses.

Antigen cross-presentation

The process by which antigen-presenting cells take up, process and present extracellular peptides on MHC class I molecules.

Metastasis-associated macrophages

(MAMs). Macrophages that accumulate in metastatic tissue that are distinct from the resident macrophages normally present in the tissue.

Myelopoiesis

The development of immune cells of the myeloid lineage (including monocytes and neutrophils) from bone marrow progenitor cells via a series of progressively lineage-committed steps.

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Garner, H., de Visser, K.E. Immune crosstalk in cancer progression and metastatic spread: a complex conversation. Nat Rev Immunol 20, 483–497 (2020). https://doi.org/10.1038/s41577-019-0271-z

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