REVIEWS Type I interferons in anticancer immunity Laurence Zitvogel1–4*, Lorenzo Galluzzi1,5–8*, Oliver Kepp5–9, Mark J. Smyth10,11 and Guido Kroemer5–9,12 Abstract | 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 1Gustave Roussy Cancer Campus, F-94800 Villejuif, viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the France. intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with 2INSERM, U1015, F-94800 Villejuif, France. favourable disease outcome in several cohorts of patients with cancer. Finally, new 3Université Paris Sud/Paris XI, anticancer immunotherapies are being developed that are based on recombinant type I IFNs, Faculté de Médecine, F-94270 Le Kremlin Bicêtre, France. type I IFN-encoding vectors and type I IFN-expressing cells. 4Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, F-94800 Villejuif, France. Type I interferons (IFNs) were first discovered more than Type I IFNs in cancer immunosurveillance 5Equipe 11 labellisée par la half a century ago as the factors underlying viral inter­ Type I IFNs are known to mediate antineoplastic effects Ligue Nationale contre le ference — that is, the ability of a primary viral infection against several malignancies, which is a clinically rel­ Cancer, Centre de Recherche 1 des Cordeliers, F-75006 Paris, to render cells resistant to a second distinct virus . Type I evant activity that has been attributed to their immuno­ 8 France. IFNs comprise IFNα proteins (a class of homologous pro­ stimulatory functions . However, the precise role of type I 6INSERM, U1138, F-75006 teins that are encoded by 13 distinct genes in humans, IFNs in the natural immune response to cancer has only Paris, France. IFNA1 to IFNA13), IFNβ (that is encoded by a single begun to be understood in the past decade. Experimental 7 Université Paris Descartes/ gene in humans and mice, IFNB1) and other, less investi­ data strongly suggest the existence of a process whereby Paris V, Sorbonne Paris Cité, F-75006 Paris, France. gated IFNs, such as IFNε, IFNκ and IFNω, which will not the immune system, in the absence of external manipula­ 2,3 8Université Pierre et Marie be discussed in this Review . Type I IFNs are produced tions, protects the host against oncogenesis and controls Curie/Paris VI, F-75006 Paris, by multiple cell types following activation of pattern the immunological features of developing tumours9. This France. recognition receptors (PRRs) (BOX 1). PRRs respond to process, which has been called cancer immunoediting, 9Metabolomics and Cell Biology Platforms, Gustave viral or bacterial components and also to endogenous consists of three phases: first, the elimination of malig­ Roussy Cancer Campus, mole­cules found in ectopic locations (such as cytosolic nant cells by the immune system; second, the establish­ F-94800 Villejuif, France. DNA and extracellular DNA and RNA)4. Type I IFNs ment of an equilibrium between genetically unstable 10Immunology in Cancer and signal via a homodimeric IFNα/β receptor 1 (IFNAR1), malignant cells and the immune system, which reflects Infection Laboratory, QIMR which has a particularly high affinity for IFNβ, or via the immunoediting imposed by the immune system Berghofer Medical Research Institute, Herston QLD 4006, an IFNAR1–IFNAR2 heterodimer, which binds all type I on cancer cells; and third, the escape of neoplastic cell Australia. IFNs. The activation of these receptors elicits many variants with reduced immunogenicity, which ulti­ 11School of Medicine, immunostimulatory effects (BOX 2) following the tran­ mately form clinically manifest neoplasms10. Type I IFNs University of Queensland, scriptional upregulation of IFN-stimulated genes (ISGs), intervene in all of these phases11,12. Herston QLD 4006, Australia. 5–7 12Pôle de Biologie, Hôpital some of which are also responsible for viral interference . At least some cell types produce type I IFNs and/or Européen Georges Pompidou, In this Review, we discuss the growing body of evi­ respond to them to avoid neoplastic transformation. AP‑HP, F-75015 Paris, France. dence suggesting that type I IFNs have a major role Indeed, the absence of Ifnb1 or Ifnar1 predisposes mouse *These authors contributed not only in antiviral immune responses but also in the embryonic fibroblasts to cellular transformation13, and equally to this work. natural and the therapy-induced immunological control some viral oncoproteins interfere with the functions of Correspondence to G.K. 14 e‑mail: [email protected] of virus-unrelated malignancies. These advances have ISGs . The tissue-specific deletion of Ifnar1 from intes­ doi:10.1038/nri3845 far-reaching implications for tumour immunology, drug tinal epithelial cells increases tumour burden in mice Published online 1 June 2015 development and clinical oncology. treated with the colitis-inducing agent dextran sodium NATURE REVIEWS | IMMUNOLOGY VOLUME 15 | JULY 2015 | 405 © 2015 Macmillan Publishers Limited. All rights reserved REVIEWS Box 1 | Sources and signals underlying type I IFN production The knockout of Ifnar1 or Ifnar2 increases the inci­ dence of methylcholanthrene (MCA)-induced fibro­ Plasmacytoid DCs (pDCs) produce high amounts of type I interferons (IFNs) following sarcomas in mice11,18. In this context, IFNAR1 must stimulation of Toll-like receptor 7 (TLR7) and TLR9, which detect viral RNA and DNA be expressed by the radiosensitive haematopoietic cell molecules, respectively, that have been endocytosed or sequestered by autophagy103. compartment to participate in immunosurveillance. pDCs are also capable of sensing host-derived nucleic acids; for instance, this occurs −/− in the context of skin wounds104. In this setting, the host DNA binds to cathelicidin Moreover, some MCA-induced Ifnar1 fibrosarcoma peptides, which promote the access of the nucleic acids to intracellular TLRs and cells were unable to form tumours following transfer to hence contribute to early inflammatory responses and re-epithelialization104. wild-type mice because they were rejected by the host (in Other sources of type I IFNs are well characterized. For instance, CD141+ which type I IFN signalling is intact)11. Taken together conventional DCs are prominent producers of IFNα in humanized mice following with the results obtained from models of mammary administration of polyinosinic–polycytidylic acid (polyI:C)105. Moreover, almost any carcinogenesis17, these findings suggest that in many cell in the body can synthesize type I IFNs upon activation of cytosolic receptors for instances cancer immunosurveillance does not rely double-stranded RNA (dsRNA), particularly the RNA helicases retinoic acid-inducible on the induction of IFNAR1 signalling in cancer cells. gene protein I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5). −/− + + Accordingly, Ifnar1 CD8α dendritic cells (CD8α DCs) RIG-I and MDA5 signal through mitochondrial antiviral-signalling protein (MAVS) and are deficient in antigen cross-­presentation, and mice TANK-binding kinase 1 (TBK1) to activate the IFN-regulatory factor 3 (IRF3)‑dependent transcription of type I IFN-coding genes2. Similarly, type I IFN can be produced upon lacking Ifnar1 only in this cellular compartment fail 19 the activation of stimulator of IFN genes protein (STING) and MAVS by the bacterial to reject highly immunogenic malignant cells . These second messenger cyclic di-GMP24. STING is also required for apoptotic thymocytes to results indicate that type I IFN signalling is a crucial com­ synthesize immunosuppressive factors, such as indoleamine 2,3‑dioxygenase 1 (IDO1), ponent of the innate immune response to transformed interleukin‑10 (IL‑10) and transforming growth factor‑β1 (TGFβ1), in vivo100, probably cells. Of note, this study19 identified a link between type I owing to its ability to drive type I IFN production. Consistent with this idea, type I IFNs IFNs and CD8α+ DCs that could explain the require­ stimulate the release of IL‑10 from regulatory T (TReg) cells and T regulatory type 1 cells ment for this antigen-presenting cell (APC) subset in (T 1 cells) in mice and humans106,107. Of note, the production of type I IFNs can be + R the spontaneous cross-priming of tumour-specific CD8 amplified by a positive feedback loop that involves the transactivation of IRF7 and, cytotoxic T lymphocytes (CTLs) in vivo20. Interestingly, at least in DCs, IRF8 in response to IFN / receptor (IFNAR) signalling. α β Reis e Sousa and colleagues21,22 showed a role for C‑type Cell death can influence immune responses as it is associated with the emission of danger signals that activate antigen-presenting cells (APCs). Several possible pattern lectin domain family 9 member A (CLEC9A) — which is + recognition receptors (PRRs) — including STING and TLRs, as well as C‑type lectin a plasma membrane receptor highly expressed by CD8α domain family 9 member A (CLEC9A) — and the autophagy-facilitated transfer of DCs — in the cross-­presentation of antigens from dying dead cell-associated antigens to APCs may be involved in the induction of type I IFNs and virus-infected cells, making it logical to pursue a in vivo25,108,109.