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Mechanisms and functional significance of tumour-induced dendritic-cell defects

Nature Reviews Immunology volume 4, pages 941–952 (2004)Cite this article

Key Points

  • Dendritic cells (DCs) are crucial for the induction of a potent immune response.

  • The dysfunction of DCs in cancer is caused mainly by abnormalities in their differentiation.

  • These abnormalities include decreased production of mature DCs, accumulation of immature DCs and accumulation of immature myeloid cells.

  • Tumour cells produce several factors that affect DC differentiation. These factors include vascular endothelial growth factor, interleukin-10 (IL-10), granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-6 and M-CSF.

  • These factors might converge on a common signal-transduction pathway — the JAK2 (Janus activated kinase 2)–STAT3 (signal transducer and activator of transcription 3) pathway.

  • Hyperactivation of STAT3 in haematopoietic progenitor cells results in the accumulation of immature myeloid cells that cannot differentiate into DCs.

  • STAT3 might exert its effect on DC differentiation by inhibiting activation of nuclear factor-κB.

Abstract

The failure of the immune system to provide protection against tumour cells is an important immunological problem. It is now evident that inadequate function of the host immune system is one of the main mechanisms by which tumours escape from immune control, as well as an important factor that limits the success of cancer immunotherapy. In recent years, it has become increasingly clear that defects in dendritic cells have a crucial role in non-responsiveness to tumours. This article focuses on the functional consequences and recently described mechanisms of the dendritic-cell defects in cancer.

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Figure 1: Outline of normal DC differentiation and the role of DCs in antitumour immunity.
Figure 2: Functional consequences of abnormal DC differentiation in cancer.
Figure 3: Model of STAT3-mediated signalling in abnormal differentiation of DCs.
Figure 4: Involvement of NF-κB in abnormal DC differentiation in cancer.

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Acknowledgements

I thank members of my laboratory for valuable discussions and the National Institutes of Health (Bethesda, United States) for supporting my research.

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  1. H. Lee Moffitt Cancer Center, University of South Florida, MRC 2067, 12902 Magnolia Drive, Tampa, 33612, Florida, USA

    Dmitry Gabrilovich

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DATABASES

Entrez Gene

CD11b

GM-CSF

GR1

IL-6

IL-10

JAK2

M-CSF

STAT3

VEGF

Glossary

ANERGY

A state of non-responsiveness to antigen. Anergic T or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.

LANGERHANS CELLS

Professional antigen-presenting dendritic cells that are localized in the skin epidermis.

SRC HOMOLOGY 2 DOMAIN

(SH2 domain). A protein domain that is commonly found in signal-transduction molecules. It interacts specifically with phosphotyrosine-containing sequences.

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Gabrilovich, D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4, 941–952 (2004). https://doi.org/10.1038/nri1498

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