Antitumour actions of interferons: implications for cancer therapy

Journal name:
Nature Reviews Cancer
Volume:
16,
Pages:
131–144
Year published:
DOI:
doi:10.1038/nrc.2016.14
Published online

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.

At a glance

Figures

  1. Crosstalk of the intrinsic and extrinsic antitumour actions of interferons.
    Figure 1: Crosstalk of the intrinsic and extrinsic antitumour actions of interferons.

    Type I interferons (IFNs) activate antitumour immunity. This extrinsic activity includes stimulation of the innate and adaptive cytotoxic lymphocyte populations (T cells, natural killer (NK) cells, dendritic cells, innate lymphoid cells (ILCs)) and the negative regulation of suppressive cell types known to dampen antitumour immunity (for example, myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells). Type I IFNs also have an intrinsic impact on tumour cells by inhibiting proliferation, and modulating apoptosis, differentiation, migration and cell surface antigen expression. Type I IFNs can be produced by both tumour and immune cells, resulting in activation of immune cells, the actions of which will depend on, or complement, tumour cell intrinsic effects, including antigen presentation, cytokine production and death signalling pathways. As such, the effect of type I IFNs on the reciprocal crosstalk between immune and tumour cells is key to their antitumour potential. The source, inducer, subtype, dose, duration and stability of the endogenous or exogenous IFN also have a major impact on outcome; as does the requirement for IFNα/β receptor (IFNAR) expression.

  2. Signalling pathways of the interferons that mediate antitumour responses.
    Figure 2: Signalling pathways of the interferons that mediate antitumour responses.

    The different types of interferon (IFN) are produced in response to damage-associated molecular patterns (DAMPs) (IFN types I and III) and cytokines (IFN type II).Each type of IFN engages its specific cognate receptor, which is pre-associated with a pair of kinases (Janus kinases (JAKs)) that phosphorylate receptors and recruit signal transducer and activator of transcription (STAT) factors that homodimerize and heterodimerize to form transcriptional activator complexes. These complexes translocate to the nucleus where they bind to specific elements in the promoters of regulated genes (for example, IFN-sensitive response element (ISRE) for the IFN gene stimulated 3 (ISGF3) complex and gamma activated sequence (GAS) elements for STAT1 and STAT3 dimers) . Type I IFNs can activate all members of the STAT family as well as other non-STAT pathways (including CRK-like (CRKL), insulin receptor substrate (IRS) and others yet to be characterized). Type I, type II and type III IFNs activate STAT1 and STAT3 dimers. To date, type III IFN has been shown to drive only pathways that are activated by type I IFN. These various signalling pathways regulate the expression of potentially thousands of genes that encode effector proteins that mediate characteristic antiviral activities as well as tumour cell intrinsic and extrinsic immunoregulatory effects. Groups of IFN-regulated genes (IRGs) comprise the 'signatures' that can be indicative of the upstream signalling pathway(s) and reflect the type of cellular response downstream. CDK, cyclin-dependent kinase; CSF1R, colony-stimulating factor 1 receptor; FASL, FAS ligand; IFNAR, IFNα/β receptor; IFNGR, IFNγ receptor; IFNLR, IFNλ receptor; IL, interleukin; IRF, IFN regulatory factor; MHC I, major histocompatibility complex class I; Mx, IFN-induced GTP-binding protein; 2'-5'-OAS, 2'-5'-oligoadenylate synthetase; PD1, programmed cell death 1, PDL1, PD1 ligand; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand; TYK2, tyrosine kinase 2.

  3. Interferons stimulate multifaceted antitumour immunity.
    Figure 3: Interferons stimulate multifaceted antitumour immunity.

    Interferons (IFNs) can be produced by tumour cells and immune cells alike, and can affect the behaviour of cells in the tumour microenvironment. The cells and mechanisms responsible for this endogenous IFN production are still being defined in this context, although it is known that innate sensing of danger-associated molecular patterns (DAMPs) (see Box 1) can be enhanced with chemotherapy (see Box 2), leading to local IFN production. Endogenous IFN production can also be induced therapeutically through the administration of pattern recognition receptor (PRR) agonists. Both endogenous and exogenous (as a result of IFN therapy) type I and type II IFNs play major roles in activating anticancer immunity (such as promoting the activity of α/β T cells, γ/δ T cells, natural killer (NK) cells and dendritic cells (DCs)), as well as inhibiting the activity of immune-suppressive cells (such as regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs)) and the conversion of tumour-associated macrophages (TAMs)). Type I and type II IFNs may also act directly on the tumour cell to improve antigen expression and to upregulate numerous immune-interacting molecules (such as major histocompatibility complex class I (MHC I) and stress ligands recognized by germline-encoded immunoreceptors). Note that although many of these pathways and mechanisms overlap and synergize, the role of B cells in antitumour immunity is contentious. In addition to B cells being positively correlated with ovarian cancer outcomes200, others suggest that this cell type promotes tumour progression in various mouse models201, 202. cAMP, cyclic AMP; IL, interleukin.

  4. Timeline of reported results of interferon use in breast cancer.
    Figure 4: Timeline of reported results of interferon use in breast cancer.

    Timeline of interferon (IFN)-based therapies and combinations trialled in patients with breast cancer in the metastatic and adjuvant treatment setting. RR, response rate, which incorporates complete and partial response (%). Survival benefits represent improved relapse-free survival or added benefit (RR) in randomized trials. CMF, cyclophosphamide, methotrexate and 5-fluorouracil (5-FU); ER, oestrogen receptor; G-CSF, granulocyte-colony-stimulating factor; IL, interleukin; RA, retinoic acid.

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Author information

  1. These authors contributed equally to this manuscript.

    • Belinda S. Parker &
    • Jai Rautela

Affiliations

  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.

    • Belinda S. Parker &
    • Jai Rautela
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.

    • Jai Rautela
  3. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

    • Jai Rautela
  4. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

    • Paul J. Hertzog
  5. Department of Molecular and Translational Sciences, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.

    • Paul J. Hertzog

Competing interests statement

The authors declare no competing interests.

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Author details

  • Belinda S. Parker

    Belinda S. Parker heads the Cancer Microenvironment and Immunology Laboratory at La Trobe University, Melbourne, Australia, and her research focuses on dissecting the interactions between tumour cells and the surrounding 'normal cells' that promote cancer invasion and metastasis. Findings by her group support key roles for tumour cell-induced immune signalling in blocking the spread of breast and prostate cancer to bone. Belinda Parker's lab page.

  • Jai Rautela

    Jai Rautela is in the final stages of his Ph.D. studies in the Cancer Microenivronment and Immunology laboratory led by Belinda S. Parker, through the Sir Peter Mac Callum Department of Oncology, University of Melbourne, Australia. He is interested in the role of cytokines in tumour immunity and immunotherapy.

  • Paul J. Hertzog

    Paul J. Hertzog is head of the Centre for Innate Immunity and Infectious Diseases at the Hudson Institute of Medical Research, Clayton, Victoria, Australia and leads a group working on innate immune signalling, in particular, the type I interferon family of cytokines, and how they modulate immune responses in cancer and infectious and inflammatory diseases.

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