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Antitumour actions of interferons: implications for cancer therapy

Key Points

  • A thorough review of the literature on interferon (IFN) use in cancer, using breast cancer as a case study, with discussion of the few clinical studies with sufficient numbers and sufficiently robust design to draw any conclusions. The clinical successes of IFNs (in other cancers) are often in blood-borne cancers and/or the setting of low tumour burden.

  • New understanding of the immune response to tumours and its regulation by the different types of IFN provides exciting opportunities for redesigning when and how IFNs can be used in the clinic.

  • IFNs are produced by various cell types in the tumour microenvironment, where they can have direct effects on tumour cells or indirect effects via modulation of the immune response.

  • Technology-driven improvements in measuring IFN responses via transcriptomics (and potentially proteomics) provides insights into the signal transduction pathways activated or inactivated during tumorigenesis. They also provide 'signatures' that can indicate the potential responsivity of patients to particular forms of therapy, including IFN.

  • A telling example is the discovery that tumour-cell-derived, IRF7-driven, type I IFN activates the immune system to target the process of metastasis. This paves the way for the use of IFN therapy in an adjuvant setting.

  • There are indications requiring further study that IFN may work well in combination with other immune-based therapies (for example, checkpoint inhibitors that target the programmed cell death protein PD1 or its ligand, PDL1) or hormonal therapies for which synergistic effects might be expected because components of partner pathways are themselves IFN regulated.

Abstract

The interferons (IFNs) are a family of cytokines that protect against disease by direct effects on target cells and by activating immune responses. The production and actions of IFNs are finely tuned to achieve maximal protection and avoid the potential toxicity associated with excessive responses. IFNs are back in the spotlight owing to mounting evidence that is reshaping how we can exploit this pathway therapeutically. As IFNs can be produced by, and act on, both tumour cells and immune cells, understanding this reciprocal interaction will enable the development of improved single-agent or combination therapies that exploit IFN pathways and new 'omics'-based biomarkers to indicate responsive patients.

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Figure 1: Crosstalk of the intrinsic and extrinsic antitumour actions of interferons.
Figure 2: Signalling pathways of the interferons that mediate antitumour responses.
Figure 3: Interferons stimulate multifaceted antitumour immunity.
Figure 4: Timeline of reported results of interferon use in breast cancer.

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Acknowledgements

This work was supported by grant funding from the Cancer Council Victoria (B.S.P. and P.J.H.), the National Health and Medical Research Council of Australia (NHMRC) (B.S.P. and P.J.H., GNT1047747), Prostate Cancer Foundation Australia (B.S.P.), fellowship support from NHMRC and ARC (B.S.P., ARC FT130100671; P.J.H., NHMRC GNT1027020) and the Victorian Government's Operational Infrastructure Support Program. The authors are grateful to R. Smith for assistance with editing this manuscript.

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Glossary

Pattern recognition receptor

(PRR). Member of a family of germline-encoded receptors expressed by most cells in the body that are capable of sensing pathogens and aberrant 'self' molecules to initiate inflammatory signalling cascades.

Plasmacytoid dendritic cells

(pDCs). A morphologically distinct population of dendritic cells found in the circulation and lymphoid organs that are particularly high producers of type I interferon (IFN) (predominantly IFNα) in response to pattern recognition receptor stimulation.

Danger-associated molecular patterns

(DAMPs). Refers to both pathogen-associated molecular patterns (PAMPs) and host-derived molecules released from injured or dying cells that activate pattern recognition receptors and the ensuing immune responses.

poly(I:C)

A synthetic double-stranded RNA mimetic. Poly(I:C) triggers pattern recognition receptor activation and is used to mimic viral RNA.

Regulatory T (Treg) cells

A population of CD4+ T cells that restrain the activity of effector T cells to prevent immune-mediated pathology, but also promote cancer by suppressing antitumour immunity.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of immature myeloid cells that expand in number in cancer and settings of chronic inflammation, and have several pro-tumour functions including suppression of the immune response.

Immune checkpoints

A diverse array of inhibitory pathways that maintain self-tolerance and appropriate immune function. However, therapeutic blockade of these pathways has recently proved highly effective in promoting tumour immunity.

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Parker, B., Rautela, J. & Hertzog, P. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer 16, 131–144 (2016). https://doi.org/10.1038/nrc.2016.14

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