The type I interferon (IFN) system involves a single form of IFNβ, several variants of IFNα and other less well-characterized IFNs, all of which signal via a heterodimeric IFNα/β receptor 1 (IFNAR1)–IFNAR2 receptor to transactivate IFN-stimulated genes (ISGs). IFNβ also promotes the transactivation of ISGs through homodimeric IFNAR1.
The secretion of type I IFNs is stimulated by viral constituents, as well as by danger signals emitted by dying cells, including nuclear and mitochondrial nucleic acids found at ectopic locations. The production of type I IFNs has marked antiviral and immunostimulatory effects.
Beyond their role in curtailing viral infection, type I IFNs play an essential part in natural cancer immunosurveillance, functioning both at the level of malignant cell precursors and through effects on the immune system. Thus, the knockout of Ifnar1 in mouse epithelial cells predisposes them to malignant transformation, as does the knockout of Ifnar1 in leukocytes, especially dendritic cells.
Type I IFN signalling is also essential for the full-blown efficacy of various anticancer agents, including chemotherapeutics (such as anthracyclines), antibodies that target growth factor receptors (such as human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR)), the injection of adjuvants and oncolytic virotherapy.
The expression levels of ISGs constitute a positive prognostic or predictive biomarker in patients affected by several cancers including melanoma and breast carcinoma. Recombinant type I IFNs have been successfully used for the treatment of various human neoplasms, particularly ulcerative melanoma, renal cell carcinoma and hepatitis B virus (HBV)-induced hepatocellular carcinoma.
Preclinical data identify four distinct approaches to improve the targeted delivery of type I IFNs to malignant lesions: first, fusing or linking recombinant type I IFNs to antibodies specific for tumour-associated surface antigens; second, engineering leukocytes or mesenchymal stem cells to express type I IFNs once they have infiltrated neoplastic lesions; third, injecting type I IFN-encoding vectors into the tumour mass; and fourth, supplying artificial ligands of type I IFN-stimulating pattern recognition receptors (PRRs).
Type I interferons (IFNs) are known for their key role in antiviral immune responses. In this Review, we discuss accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance. Many conventional chemotherapeutics, targeted anticancer agents, immunological adjuvants and oncolytic viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with favourable disease outcome in several cohorts of patients with cancer. Finally, new anticancer immunotherapies are being developed that are based on recombinant type I IFNs, type I IFN-encoding vectors and type I IFN-expressing cells.
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The authors are indebted to J. M. Bravo-San Pedro (Centre de Recherche des Cordelies, Paris, France) for help with figure preparation. G.K. and L.Z. are supported by the Ligue contre le Cancer (Équipe Labelisée); Agence Nationale de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la Recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); the Paris Alliance of Cancer Research Institutes (PACRI); and the ISREC and Swiss Bridge Foundations. M.J.S. is supported by the National Health and Medical Research Council of Australia (NH&MRC); the Cancer Council of Queensland; QIMR Berghofer Medical Research Institute; and the Susan G. Komen foundation.
The authors declare no competing financial interests.
- Pattern recognition receptors
(PRRs). Evolutionarily old receptors expressed by cells of the innate immune system. PRRs detect viral and bacterial components that are commonly referred to as microorganism-associated molecular patterns (MAMPs), as well as endogenous molecules known as damage-associated molecular patterns (DAMPs). PRRs constitute key sensors of danger.
- T regulatory type 1 cells
(TR1 cells). A subset of immunosuppressive CD4+ T cells that downregulate T helper 1 (TH1) and TH2 cell responses in vitro and in vivo by a contact-independent mechanism that is mediated by the secretion of soluble interleukin-10 and transforming growth factor-β1.
- CD8α+ dendritic cells
(CD8α+ DCs). A DC subset phenotypically characterized by the expression of Cd8a (in mice) and particularly efficient at cross-presentation: that is, at presenting extracellular antigens on MHC class I molecules to CD8+ cytotoxic T cells, rather than on MHC class II molecules to CD4+ T helper cells.
The initiation of a CD8+ T cell response against an antigen that is not expressed by antigen-presenting cells (APCs). Cross-priming relies on the ability of some APCs to redirect internalized antigens to the MHC class I presentation pathway (cross-presentation).
- Stimulator of IFN genes protein
(STING). A protein of the endoplasmic reticulum membrane (encoded by TMEM173) that promotes the production of type I interferons (IFNs) in response to cyclic di-GMP and works as an adaptor in the signal transduction cascades induced by other cytosolic sensors of nucleic acids.
- Plasmacytoid DCs
(pDCs). A dendritic cell (DC) subset that is phenotypically characterized by reduced expression levels of CD11c and CD14 and that is particularly efficient at type I interferon production in response to several stimuli.
(GVL). The process by which allogeneic haematopoietic stem cell grafts recognize (and eliminate) residual leukaemic cells in the host as a result of some degree of mismatch between minor histocompatibility antigens.
- Cytotoxic T lymphocyte-associated protein 4
(CTLA4). A plasma membrane receptor of the immunoglobulin superfamily that is expressed by activated T cells. It is involved in the physiological extinction of immune responses but is also harnessed by malignant cells to establish an immunosuppressive tumour microenvironment.
- Programmed cell death protein 1
(PD1). Plasma membrane receptor of the immunoglobulin superfamily expressed by activated T cells, B cells and macrophages. Similar to cytotoxic T lymphocyte-associated protein 4 (CTLA4), PD1 is harnessed by cancer cells for the establishment of local and systemic immunosuppression.
- Immunomodulatory drugs
(IMiDs). A group of molecules with immunomodulatory effects currently approved for the treatment of erythema nodosum leprosum (a complication of leprosy), multiple myeloma and myelodysplastic syndrome. IMiDs include thalidomide, lenalidomide and pomalidomide.
- Anticancer virotherapy
A peculiar paradigm of anticancer immunotherapy based on the administration of natural or genetically modified viruses that selectively kill malignant cells.
- Pegylated IFN
Recombinant interferon (IFN) modified by the addition of a polyethylene glycol (PEG) moiety. This modification improves the half-life of recombinant IFN in the circulation.
- Retinoic acid-inducible gene I
(RIG-I). A cytosolic sensor that responds to viral double-stranded RNA in the cytosol by inducing type I interferon production.
A multikinase inhibitor initially developed as a specific blocker of BCR–ABL, the chimeric kinase that aetiologically underpins leukaemogenesis in Philadelphia chromosome- bearing cells. As imatinib also inhibits KIT and platelet- derived growth factor receptor-β (PDGFRβ; encoded by PDGFRB), it is also used in patients with gastrointestinal stromal tumours that overexpress KIT and some myelodysplastic syndromes associated with PDGFRB rearrangements.
- Induced pluripotent stem cells
(iPSCs). A type of pluripotent stem cell that can be generated directly from adult mature cells. Once they have been obtained, iPSCs can be differentiated into almost any cell type.
- Indoleamine 2,3-dioxygenase 1
(IDO1). An enzyme that catalyses the first and rate-limiting reaction of degradation of the amino acid L-tryptophan. IDO1 mediates robust immunosuppressive effects, not all of which depend on its ability to deplete L-tryptophan and favour the accumulation of L-kynurenine.
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Zitvogel, L., Galluzzi, L., Kepp, O. et al. Type I interferons in anticancer immunity. Nat Rev Immunol 15, 405–414 (2015). https://doi.org/10.1038/nri3845
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