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  • Review Article
  • Published:

Interferons, immunity and cancer immunoediting

Key Points

  • The cancer-immunoediting hypothesis emphasizes that extrinsic immune pressure either can block tumour growth, development and survival or can facilitate tumour outgrowth (by sculpting tumour immunogenicity or by inhibiting host-protective antitumour immune responses). The acquired capacity of developing tumours to escape immune control is a seventh hallmark of cancer.

  • The interferons (IFNs) — both type I IFNs (IFNα and IFNβ) and type II IFN (IFNγ) — have long been recognized as pivotal antiviral and antimicrobial molecules. However, considerable evidence from physiologically relevant tumour models reveals that these molecules also have important roles in protecting the host against tumour development.

  • Endogenously produced IFNγ affects tumour cells directly during the antitumour immune response. IFNγ promotes tumour recognition by increasing the activity of the MHC class I pathway and by modulating the expression of ligands of NKG2D (natural-killer group 2, member D). IFNγ also affects the host immune system by polarization of T helper (TH) cells towards a TH1-cell phenotype, by induction of cytotoxic T lymphocytes and by inhibition of CD4+CD25+ regulatory T-cell development.

  • By contrast, endogenously produced type I IFNs do not act on tumour cells but, instead, on host haematopoietic cells, resulting in inhibition of tumour growth. Similar to tumours that are generated in mice that lack lymphocytes (recombination-activating gene 2 (RAG2)-deficient mice), tumours from mice that lack the IFNAR1 subunit of the type I IFN receptor are highly immunogenic and are therefore 'unedited'.

  • At present, type I IFNs are the only IFNs that are routinely used in a clinical setting for the treatment of cancer patients. Future work focused on controlling local delivery, identifying physiologically relevant IFN-producing cells and identifying IFN-dependent antitumour mechanisms will be vital to translate the well-established antitumour properties of the IFNs from animal modelsto the clinic.

Abstract

A clear picture of the dynamic relationship between the host immune system and cancer is emerging as the cells and molecules that participate in naturally occurring antitumour immune responses are being identified. The interferons (IFNs) — that is, the type I IFNs (IFNα and IFNβ) and type II IFN (IFNγ) — have emerged as central coordinators of tumour–immune-system interactions. Indeed, the decade-old finding that IFNγ has a pivotal role in promoting antitumour responses became the focus for a renewed interest in the largely abandoned concept of cancer immunosurveillance. More recently, type I IFNs have been found to have distinct functions in this process. In this Review, we discuss the roles of the IFNs, not only in cancer immunosurveillance but also in the broader process of cancer immunoediting.

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Figure 1: Cancer immunoediting.
Figure 2: Interferon-induced signalling and transcription.

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Acknowledgements

The authors are grateful to the following individuals: L. J. Old and M. J. Smyth for past and continuing collaborations and for critical comment during the preparation of this Review; G. P. Linette for helpful comment on the clinical use of IFNs in cancer immunotherapy; and all past and present members of the Schreiber laboratory for their essential contributions to the development of the cancer-immunoediting hypothesis. This work was supported by grants from the National Cancer Institute (United States), the Ludwig Institute for Cancer Research (United States) and the Cancer Research Institute (United States).

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List of approved oncology drugs with approved indications

Glossary

Transformation

The process of conversion of a normal cell into a cancer cell.

Cancer immunosurveillance

Immunological protection of the host against the development of cancer, resulting from immune effector functions stimulated by immune recognition of either stress ligands or antigens expressed on transformed cells.

Hallmarks of cancer

A specific set of features that must be acquired by a malignant cell. These features are self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptotic cell death, limitless replicative potential, sustained angiogenesis, tissue invasion and evasion of the antitumour immune response.

Primary tumorigenesis

Transformation and tumour formation that occurs entirely in the original host, in contrast to tumour formation in a host owing to transplantation of cells that were transformed in another host or in vitro.

γδ T cell

T cells express either a T-cell receptor (TCR) composed of an α-subunit and a β-subunit (αβ-TCR) or a TCR composed of a γ-subunit and a δ-subunit (γδ-TCR). T cells that express αβ-TCRs mainly recognize antigenic peptides bound to conventional MHC class I or class II molecules. T cells that express γδ-TCRs are less abundant, and the ligands for these receptors are less well characterized.

Natural killer T cell

(NKT cell). A T cell that expresses both natural killer (NK)-cell receptors and an αβ T-cell receptor. NKT cells are characterized by cytolytic activity and by rapid production of cytokines (including interferon-γ and interleukin-4), and they might regulate the function of other T cells.

Epigenetic

Any heritable influence on the function of a chromosome or gene that is not caused by a change in DNA sequence.

Regressor tumour

A cell line derived from a primary tumour that is rejected when transplanted into naive syngeneic hosts that are immunocompetent but grows progressively in syngeneic hosts that are immunocompromised.

Angiostatic molecule

A molecule that blocks or opposes the growth of blood vessels and the formation of new blood vessels.

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Dunn, G., Koebel, C. & Schreiber, R. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6, 836–848 (2006). https://doi.org/10.1038/nri1961

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