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  • Review Article
  • Published:

Immune cell promotion of metastasis

Nature Reviews Immunology volume 15, pages 73–86 (2015)Cite this article

Subjects

Key Points

  • Malignant tumour cells avoid immune attack by cytotoxic immune cells in the primary tumour site by modulating tumour-infiltrating leukocytes, such as myeloid cells and regulatory T (TReg) cells, which can enhance the survival of tumour cells and can promote their dissemination to the metastatic site.

  • Some types of primary tumour secrete systemic factors that recruit immature myeloid cells to the future metastatic site. Establishment of this pre-metastatic niche enhances efficacy of tumour metastasis.

  • Egress from the primary site is promoted by tumour-associated macrophages (TAMs) that increase angiogenesis, enhance tumour cell mobility and invasiveness, and promote extracellular matrix remodelling. TAMs therefore accelerate tumour cell intravasation and systemic tumour cell dissemination.

  • The survival of circulating or arrested tumour cells is increased by platelets, TAMs and TReg cells. These immune cells transmit survival signals and protect tumour cells from immune attack, which promotes the establishment of metastatic foci.

  • A distinct subset of TAMs, termed metastasis-associated macrophages, promotes extravasation and metastatic growth of cancer cells at the metastatic site.

  • Targeting pro-metastatic immune cells, especially macrophages, by neutralizing colony-stimulating factor 1 (CSF1) or CC-chemokine ligand 2 (CCL2), will be an attractive therapeutic strategy.

  • Emerging data suggest that a combination of conventional immunotherapy or chemotherapy and macrophage-modulating therapy may be effective to control or eradicate metastatic cancer.

Abstract

Metastatic disease is the major cause of death from cancer, and immunotherapy and chemotherapy have had limited success in reversing its progression. Data from mouse models suggest that the recruitment of immunosuppressive cells to tumours protects metastatic cancer cells from surveillance by killer cells, which nullifies the effects of immunotherapy and thus establishes metastasis. Furthermore, in most cases, tumour-infiltrating immune cells differentiate into cells that promote each step of the metastatic cascade and thus are novel targets for therapy. In this Review, we describe how tumour-infiltrating immune cells contribute to the metastatic cascade and we discuss potential therapeutic strategies to target these cells.

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Figure 1: A long journey to develop metastatic tumours.
Figure 2: Preparation for a metastatic journey.
Figure 3: Promotion of the first step of metastasis.
Figure 4: Helping to overcome the rate-limiting steps of metastasis.

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Acknowledgements

The authors apologize to all others whose work they could not cite because of space restrictions. The authors' work presented in this Review article has been supported by US National Institutes of Health grants RO1 CA172451 and PO1CA100324 and by the Wellcome Trust, UK (SIA 101067/Z/13/Z).

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Authors and Affiliations

  1. Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK

    Takanori Kitamura, Bin-Zhi Qian & Jeffrey W. Pollard

  2. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10543, New York, USA

    Jeffrey W. Pollard

Authors
  1. Takanori Kitamura
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  2. Bin-Zhi Qian
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  3. Jeffrey W. Pollard
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Correspondence to Jeffrey W. Pollard.

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Glossary

Metastasis

The spread of malignant tumour cells from the primary tumour site to distant organs (through the lymphatic system or the blood), in which they grow expansively to develop deadly secondary tumours. Individual tumours express different tissue tropisms for metastasis that may partly be due to the systemic education of different tissues to form pre-metastatic niches.

Tumour microenvironment

The tumour-surrounding environment consists of stromal cells such as endothelial cells, immune cells and fibroblasts, as well as the extracellular matrix. It also contains chemokines, cytokines and growth factors derived from tumour cells and tumour-educated stromal cells.

Regulatory T cells

(TReg cells). A distinct population of immunosuppressive CD4+ T cells that are characterized as CD25+FOXP3+.

T helper 17 cells

(TH17 cells). A subset of CD4+ T helper cells that produce interleukin-17. TH17 cells have crucial roles in adaptive immune responses to pathogens.

Regulatory B cells

(BReg cells). A subpopulation of B cells that have immunosuppressive functions and that may protect the host from autoimmune diseases. In mouse mammary tumours, CD19+B220+CD25+ cells are isolated as immunoregulatory cells and termed tumour-evoked BReg cells.

Tumour-associated macrophages

(TAMs). A distinct population of macrophages in the tumour microenvironment that promotes tumour development and progression. TAMs can be identified by the following marker profile (a marker that is unique to mouse or human is indicated by (m) or (h), respectively): CD11b+, CD14+, CD23+ (h), CD34−, CD45+, CD68+, CD117−, CD133−, CD146−, CD163+ (h), CD204+, CD206+, CCR2+, CSF1R+, CXCR4+ (h), F4/80+ (m), GR1− (m), MHC class II+, VEGFR1+ and VEGFR2−. TAM is a generic term that encompasses several identifiable subpopulations with different functions, including TIE2-expressing pro-angiogenic macrophages in the primary tumour. Thus, each population will have a set of canonical macrophage markers, such as CSF1R+GR1−, but will differentially express other markers, such as VEGFR1.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of myeloid cells, the numbers of which are increased in most patients with cancer and in animal models of cancer. These cells are subdivided into monocytic and granulocytic MDSCs.

Plasmacytoid dendritic cells

(pDCs). A small population of DCs that link innate and adaptive immune responses. Although pDCs have pro-inflammatory properties, such as cytokine secretion, they also have immunosuppressive effects. In mice, pDCs are characterized by expression of B220, CD11c, Siglec-H, PDCA1 (also known as CD317) and GR1, and by the absence of CD11b.

Osteoclastogenesis

A process whereby haematopoietic stem cells differentiate into multinucleated osteoclasts with bone-resorbing activity.

Metastasis-associated macrophages

(MAMs). A distinct subset of tumour-associated macrophages that are recruited to the metastatic sites and promote tumour cell dissemination and outgrowth. MAMs originate from inflammatory monocytes and are characterized by the following marker profile in mice: CD11b+, CD31−, CD45+, CCR2+, CXCR4−, F4/80+, LY6C−, LY6G−, TIE2−, VEGFR1+ and VEGFR2−.

Inflammatory monocytes

A subset of monocytes that is recruited to inflammatory sites. They are characterized as CD11b+LY6C+ in mice and CD14hiCD16− in humans. Inflammatory monocytes also express high level of CCR2 and CSF1R but not the neutrophil marker LY6G. In mouse tumour models, inflammatory monocytes are recruited to the primary or metastatic sites by CCL2 and differentiate into tumour-associated macrophages or metastasis-associated macrophages, respectively.

Neutrophil extracellular trap

(NET). An extracellular fibre structure that consists of extruded DNA and antimicrobial proteins released from neutrophils in response to inflammatory stimuli. A major function of NETs is to trap and kill pathogens.

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Kitamura, T., Qian, BZ. & Pollard, J. Immune cell promotion of metastasis. Nat Rev Immunol 15, 73–86 (2015). https://doi.org/10.1038/nri3789

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